Ramirez was born in Santo Domingo, Dominican Republic to Aristides and Onelcida Ramirez and spent 13 years living there. As a child, Ramirez was obsessed with baseball. When he was eight years old, his grandmother got him a Dodgers uniform with the number 30 on the back, which he considers to be one of his most prized possessions. In 1985, he moved to the Washington Heights neighborhood of New York City with his parents. He often played ball at the nearby Snake Hill, the same place Lou Gehrig played during his childhood. Despite living just a short distance from Yankee Stadium, Ramirez rooted for the Toronto Blue Jays, who had his Dominican heroes George Bell and Tony Fernández on its roster; he attended games when the Blue Jays were in town.

During his time at GWHS, he led his team to three straight division championships. He was a three-time all-city selection in baseball, and as a high school senior was named New York City Public School Player of the Year in 1991, hitting for a .650 batting average with 14 home runs in 22 games. He was inducted into the New York City Public School Athletic Hall of Fame in 1999.

With the Single-A Kinston Indians in 1992, Ramirez battled injuries but still hit .278 with 13 homers and 63 RBIs in 81 games and was named as the number three prospect and the “Most Exciting Player in the Carolina League” by Baseball America. In 1993, Ramirez was named “Minor League Player of the Year” by Baseball America while hitting .333 with 31 homers and 115 RBIs in 129 combined games with the Double-A Canton–Akron Indians and Triple-A Charlotte Knights.

Ramirez made his major league debut on September 2, 1993 against the Minnesota Twins, going hitless in four at bats as the designated hitter.

In 1994, his first full season in the majors, Ramirez had a strong start to the season, hitting six home runs during the month of April. Despite a weak start to May, he rebounded in the latter half of the month, finishing the month with a .300 batting average. During the season, the Indians were chasing the Chicago White Sox for first place in the American League Central (AL Central) division all the way until the end of the season. However, the team’s season ended in August due to the 1994 MLB strike. Ramirez finished second in the Rookie of the Year award voting after batting .269 with 17 home runs and 60 RBIs in 91 games.

Ramirez’s breakout season came in 1995, when he batted .308 with 31 home runs and 107 RBIs. In July, he was selected to his first All-Star Game and won his first career Silver Slugger Award following the season. That year, the Indians reached the postseason, and Ramirez hit two home runs in the 1995 American League Championship Series against the Mariners, which the Indians won in six games. The Indians then took on the Atlanta Braves in the World Series, and Ramirez batted .222 with one home run in the Indians’ six-game loss. In December 1995, Ramirez agreed to a $10.15 million, four-year contract.

Ramirez has often attracted attention on and off the field for his quirky and often fun-loving behavior and attitude, which is sometimes at odds with MLB’s more serious and traditional culture. These incidents are colloquially known as “Manny Moments” or, more commonly, “Manny Being Manny”. Instances of this behavior include inducing his Red Sox teammates, including Ellis Burks, to drink alcohol which he had spiked with Viagra, wearing Oakley THUMP while playing the outfield, disappearing through a door in the Green Monster to use the bathroom, diving to intercept a throw from teammate Johnny Damon in the outfield which had been intended for the infield, selling his barbecue grill on eBay, and high fiving a fan after a catch at the outfield wall before throwing the ball back to the infield to complete a double play. The first known documented usage of the phrase “Manny Being Manny” is attributed to then-Indians manager Mike Hargrove, quoted in a 1995 Newsday article.

Ramirez continued to hit well in 1996, batting .309 with 33 home runs and 112 RBIs. The Indians again reached the playoffs, and Ramirez batted .375 with 2 home runs in the Indians’ loss to the Orioles in the 1996 American League Division Series. In 1997, Ramirez’s contact continued to improve, though his power dipped slightly, as he hit .328 with 26 home runs and 88 RBIs. This year, the Indians again reached the World Series, and Ramirez batted .154 with two home runs as the Indians lost to the Florida Marlins in seven games.

In 1998, Ramirez experienced a great increase in power, on his way to becoming one of the great run producers in the game. He batted .294 with 45 home runs and 145 RBIs, and was selected to his second All-Star Game, where he recorded a sacrifice fly and RBI. Ramirez batted .357 with 2 home runs during the ALDS versus the Red Sox, which the Indians won in four games. In the ALCS against the Yankees, Ramirez batted .333 with two home runs, but the Indians lost in six games. Following the season, Ramirez came in sixth place in AL MVP voting.

Ramirez began 1999 on a hot streak, hitting .337 with 7 home runs in the month of April. Ramirez’s hot hitting continued all season, as he batted .364 in May and reached the All-Star break with 25 home runs and 96 RBIs. At the time, it was the third highest single season total for RBI by the All-Star Break in MLB history, behind only Hank Greenberg (103 in 1935) and Juan González (101 in 1998). On September 30, 1999, Ramirez broke the Indians’ single-season RBI record (previously 162 by Hal Trosky in 1936) by hitting a 3-run home run, giving Ramirez 164. Despite missing 15 games, he finished 1999 with 165 RBIs, the highest total by any player since Jimmie Foxx (1938), and batted an eye popping .383 against left handed pitchers. He also batted .383 with runners in scoring position, and .377 with men on base. That season, he finished third in the voting for the AL MVP award. However, he struggled in the 1999 postseason, going 1-for-18 as the Indians were eliminated by the Boston Red Sox in 5 games in the 1999 American League Division Series.

In 2000, Ramirez was limited to 118 games due to injuries, but recorded a career-high .351 batting average, along with 38 home runs and 122 RBIs. His return is believed to have started a major comeback that led the Indians to a final record of 90–72 and cut the number of games they were behind the leader of the AL Central, the Chicago White Sox, from 11.5 games down to 7.5 games in just a month. Because of his return, Roberto Alomar, Omar Vizquel, and Kenny Lofton all started getting better pitches to hit, which also significantly increased their batting averages. Despite the comeback, the Indians failed to make the postseason, finishing 5 games behind the White Sox in the AL Central. With free agency looming, Ramirez homered in his final game and at-bat in an Indians uniform, on October 1 against Toronto in front of the home fans at Jacobs Field.

In November 2000, the Indians offered Ramirez a seven-year, $119 million contract. While this would have made Ramirez the highest-paid player in baseball, the deal was rejected by Ramirez and his agent, Jeff Moorad, who were seeking a ten-year, $200 million contract. Ramirez was reportedly pursued by the New York Yankees and Seattle Mariners, but in December agreed to an eight-year, $160 million deal with the Boston Red Sox, with $20 million options for 2009 and 2010, pushing the total value of the contract to $200 million for 10 years.

Ramirez immediately delivered for the Red Sox, hitting .408 in April 2001. He had another sterling first half, amassing a .335 batting average with 26 home runs and 84 RBI at the 2001 All-Star break. However, he missed some time battling hamstring injuries and struggled down the stretch, finishing at .306 with 41 home runs and 125 RBI. On June 23, Ramirez hit two monstrous home runs against the Toronto Blue Jays at Fenway Park, with the second one hitting the very top of the light tower in left field. Its length was officially listed at 501 feet, second-longest by a Red Sox player in Fenway Park’s history, just short of Ted Williams’ 1946 record of 502 feet. He also launched a prodigious home run in an away game on June 3 against the Blue Jays into the fifth deck at the SkyDome, which still stands as the longest home run in that ballpark’s history at 491 feet. However, despite his efforts, the Red Sox did not qualify for the MLB postseason in 2001. Ramirez, primarily a right fielder in his career to this point, spent most of the season as the designated hitter for the Red Sox. This was due to the Red Sox’ belief that Ramirez was best suited to left field due to the presence of Trot Nixon in right, as well as the injuries Ramirez battled during the 2001 season. After signing with the Red Sox, Ramirez played only 7 more games in right field, all of which came during the 2002 season.

Ramirez only played in 120 games in 2002 due to a hamstring injury that put him on the disabled list (DL) from mid-May to the end of June. Despite this, Ramirez won the AL batting title, hitting .349 (including .438 against lefties), and his .647 slugging percentage was second in the league behind Jim Thome’s .677. Like clockwork, Ramirez again reached the 30 home run and 100 RBI plateaus, posting 33 and 107 respectively. He hit his 300th career home run on August 26 against the Angels’ Ramón Ortiz. It was the first of two home runs on the night for Ramirez, as he went 5-for-5 overall. However, the Red Sox again failed to qualify for the MLB postseason in 2002.

In 2003, Ramirez again posted strong offensive numbers, finishing with a .325 average, 37 home runs, and 104 RBI. The second half surge of newly acquired fellow Dominican slugger David Ortiz gave the Red Sox a formidable one-two punch in the middle of the lineup with Ramirez. However, in the summer, Ramirez missed several games with pharyngitis, but got into hot water as he was spotted in a bar in the hotel where he lived with a close friend, Yankees infielder Enrique Wilson, despite being supposedly too ill to play in the series against the rival Yankees. Ramirez and Wilson both maintained that Manny was just talking to his friend in that setting, and not actually drinking or partying as the media speculated. Boston manager Grady Little benched Ramirez for one game as a result. Despite this distraction, the Red Sox finished the season 95-67, qualifying for the MLB postseason for the first time with Ramirez. In the decisive fifth game of their Division Series matchup against the Oakland Athletics, Ramirez broke a 6th inning 1-1 tie by launching a go-ahead three-run homer off Barry Zito that set up an ALCS showdown with the rival Yankees. In ALCS Game 3, Ramirez was at the center of a bench-clearing brawl. Early in the game, Red Sox pitcher Pedro Martínez had hit Yankees outfielder Karim Garcia up high with a pitch, sparking heated dialogue, and a hard slide by Garcia into Red Sox second baseman Todd Walker had exacerbated the tensions. The very next inning, Yankees pitcher Roger Clemens threw a pitch high and inside to Ramirez, and Manny charged the mound, sparking the melee. The Red Sox lost the game 4-3. Despite Ramirez’s strong play in the ALCS against the Yankees (.310 with 2 home runs), the Red Sox fell to the Yankees in the decisive seventh game on Aaron Boone’s infamous extra-inning, walk-off home run.

In 2004, Ramirez led the AL in home runs (43), slugging percentage (.613) and OPS (1.009); he finished second in errors committed as a left fielder (7), third in RBIs (130), fourth in doubles (44) and total bases (348), sixth in on-base percentage (.397), eighth in walks (82), tenth in runs (108), and posted a .308 batting average. He also led the AL in salary, at $22.5 million.

In the 2004 Major League Baseball All-Star Game, Ramirez hit a two-run home run off Roger Clemens in the top of the first inning, giving his teammates a 3–0 lead. Ramirez, Derek Jeter (with a single), Ichiro Suzuki (with a double) and Iván Rodríguez (with a triple) became the first All-Star quartet that combined to hit for the cycle during the same inning. The Red Sox again qualified for the postseason, and Ramirez continued his hot hitting. He hit .385 in the 2004 ALDS, leading the Red Sox to a sweep over the Anaheim Angels, and setting up a rematch in the 2004 American League Championship Series against the Yankees. Despite not driving in a run in the ALCS, Ramirez hit .300 as the Red Sox completed a historic comeback from down 3 games to 0 to win in seven against the Yankees, setting up a showdown with the St. Louis Cardinals in the 2004 World Series as the Red Sox attempted to end the Curse of the Bambino and win their first championship since 1918. Ramirez proceeded to hit .412 with a home run and 4 RBI in a 4-game sweep of the Cardinals, as the Red Sox won their first title in 86 years. His home run came in the first inning of Game 3, off Cardinals starter Jeff Suppan, continuing a streak throughout the Series where the Red Sox scored in the first inning of each game. Ramirez’s 2004 season was capped off by being named World Series MVP. Ramirez also finished third in AL MVP voting, just ahead of teammate Ortiz, who finished fourth.

On May 10, 2004, Ramirez missed a Red Sox game to become a naturalized citizen of the United States. He entered the next game running onto the field to a standing ovation while carrying a small American flag held in his hand. He planted the flag in the left outfield corner of the field, in the shadow of the Green Monster, where it remained for the entire game.

On May 15, 2005, Ramirez hit his 400th home run off Gil Meche of the Seattle Mariners. On July 5, Ramirez hit his 20th career grand slam — and his third of the season — off Chris Young of the Texas Rangers. On defense, however, he tied for the lead among all major league left fielders in errors, with 7. He posted his highest single season RBI total as a Red Sox in 2005, driving in 144 runs to go along with his 45 homers, but he batted only .292, his first time under .300 since 1998. Along with teammate David Ortiz, who drove in 148 runs, the duo combined to drive in an outstanding 292 runs. Ortiz finished second, and Ramirez fourth, in MVP voting to winner Alex Rodriguez.

Off the field, the season was one of much conflict for Ramirez. Persistent trade rumors (generally involving the New York Mets) dogged him all season. After the Red Sox were eliminated in the first round of that year’s playoffs by the eventual World Series champion Chicago White Sox, Ramirez once again expressed a wish to be traded. This included a threat to not show up for spring training if his latest demand was not met by Red Sox GM Theo Epstein. Toward this end, in December 2005, Ramirez put his Ritz-Carlton condominium up for sale. Trade rumors circulated with Ramirez possibly going to the Baltimore Orioles or the New York Mets, but no deal was reached. By January 5, 2006, Ramirez changed his mind, stating that he was dropping the demand. His agents, in turn, insisted their client was still open to a trade. But no deal materialized.

On June 10, 2006, Ramirez became the 31st player in history to hit 450 home runs, with a solo home run off Francisco Cordero of the Texas Rangers. Three weeks later, on July 1, he collected his 2000th hit. Beginning in mid-July, he had a 28-game hitting streak, including 12 multi-hit games, 8 HR, and 28 RBIs. He reached 100 RBI for the 9th consecutive season on August 20 in a series against the Yankees, but missed 28 games from mid-August on with soreness in his right knee. Ramirez finished at .321 with 35 home runs and 102 RBI. He also drew a career high 100 walks in 2006, the only time in his career he reached that mark. However, the Red Sox missed the playoffs for the first time since the 2002 season.

On April 22, 2007, Ramirez was the first of four Red Sox batters to homer in consecutive at bats in a game against the New York Yankees pitcher Chase Wright, tying a league record when J. D. Drew, Mike Lowell, and Jason Varitek followed Ramirez with longballs of their own. On April 29, Ramirez became the fifth player to hit 50 career home runs against the Yankees.

Ramirez finished 2007 with a .296 batting average, 20 home runs, and 88 RBIs, ending his streak of 30 home run and 100 RBI seasons at 9. His season was cut short when he strained his left oblique in late August during a Yankees series, but he did return to the lineup for the final homestand of the season. In 2007, he had the highest fielding percentage (.990) among left fielders in the AL, tied for second in the major leagues; he was ranked sixth-highest in range factor of all AL left fielders, 1.72, 16th in both leagues, but had the lowest zone rating among MLB left fielders with 100+ games (.713). He made two errors during the 2007 season in left field, and tied for fifth overall in the major leagues in assists from left field.

2008 opened with Ramirez and the Red Sox defending their crown, and with Ramirez himself stating he wanted “to play six more years and then retire as a member of the Red Sox.” Ramirez played in his 2,000th game on May 26, 2008 against Seattle. On May 31, 2008, Ramirez hit his 500th home run, against Baltimore Orioles pitcher Chad Bradford at Camden Yards in the seventh inning on the first pitch. He became the 24th player in MLB history to do so. He joined two other Boston legends, Jimmie Foxx and Ted Williams, to have joined the exclusive home run club as a member of the Red Sox.

On July 31, 2008, Ramirez was traded to the Los Angeles Dodgers in a three-way deal. The Boston Red Sox acquired outfielder Jason Bay and minor league infielder Josh Wilson, and the Pittsburgh Pirates got infielder Andy LaRoche and pitching prospect Bryan Morris from the Dodgers and outfielder Brandon Moss and pitcher Craig Hansen from the Red Sox. Ramirez had always worn uniform number 24, but the Dodgers had retired that number in honor of Hall of Fame manager Walter Alston. Ramirez instead chose to wear number 99 with the Dodgers.

Ramirez began 2009 at a highly productive pace as well. Through May 7, he was batting .348 with 6 home runs and 20 RBI. But on that date, Ramirez was suspended 50 games for violating the Joint Drug Prevention and Treatment Program established by MLB and the MLB Players Association in 2004. In the announcement by MLB, Ramirez was suspended for unspecified violation of the agreement section 8.G.2. Shortly afterward, Ramirez stated that a physician had unknowingly prescribed a banned medication. After consulting with the players association, Ramirez waived his right to challenge the suspension. According to an ESPN report, the drug used by Ramirez was human chorionic gonadotropin (hCG), a women’s fertility drug typically used by steroid users to restart their body’s natural testosterone production as they come off a steroid cycle. It is similar to Clomid, the drug Jason Giambi and others used as clients of BALCO. Testing revealed artificial testosterone, too. As a condition for returning from the suspension, Ramirez was subject to three additional drug tests per year in addition to the minimum of two per player.

Manny finished 2009 with a .290 batting average, 19 home runs, and 63 RBI in 104 games. He added a home run and 4 RBI in the 2009 MLB postseason (batting .281), but the Dodgers were again eliminated by the Philadelphia Phillies in the NLCS.

On April 10, 2010, Ramirez recorded his 2,500th career base hit with an infield single against the Florida Marlins. On April 18 against the San Francisco Giants, Ramirez hit his 548th career home run to tie Mike Schmidt for the 14th place on the all-time home run list. He hit his 549th to pass Schmidt on May 28 against the Colorado Rockies. On June 19, he hit a home run in his second game back at Fenway Park.

In 2010, Ramirez had three separate stints on the disabled list. When he returned from the third trip on August 21, he apparently had lost his starting job to Scott Podsednik. As a pinch hitter, he was ejected on August 29 by home plate umpire Gary Cederstrom one pitch into his at-bat for arguing a strike call. That appearance was his final one in a Dodger uniform. He batted .311 with 8 homers and 40 RBI in only 66 games as a Dodger in 2010 before being placed on waivers.

On January 21, 2011, Ramirez agreed to a one-year, $2 million deal with the Tampa Bay Rays, who also signed his former Red Sox teammate Johnny Damon in a package deal suggested by agent Scott Boras.

The signing initially looked like a bargain as Ramirez was among the better hitters in spring training, hitting .311 with 3 home runs and 10 RBI. However, the 38-year-old Ramirez abruptly retired on April 8, 2011, after batting .059 (1-for-17) in his first five games with no home runs and a single RBI. Ramirez reportedly tested positive for a banned performance-enhancing drug in spring training. His first sample, or A sample, was retested and again returned a positive result. Ramirez filed a notice to appeal, and his second sample, or B sample, was tested under observation by Ramirez’ representatives. When the B sample also tested positive, he dropped the appeal and told MLB that he would immediately retire.

In September 2011, reports surfaced that Ramirez was planning on playing in the Dominican Winter League for the Cibao Eagles. In a statement, the team said that Ramirez hoped to motivate other MLB stars to play in the country. However, the MLB Commissioner’s Office issued a statement that since the Dominican League is affiliated with MLB, Ramirez was not eligible to play without first serving his mandated suspension.

On February 20, 2012, Ramirez signed a minor league contract with the Oakland Athletics. The deal called for a $500,000 salary if he made the MLB roster. However, he needed to serve his 50-game suspension before he could play for the team. He was eligible to play on May 30, 2012. With the Sacramento River Cats he hit .302 in 17 games, but had no homers and only a .349 slugging percentage. On June 15, Ramirez requested and was given his outright release by the Athletics.

Ramirez played in the Dominican Professional Baseball League during the 2012–13 offseason, registering a .793 OPS for the Águilas Cibaeñas. He signed with the newly renamed EDA Rhinos of the Chinese Professional Baseball League in Taiwan for the 2013 season. He made his debut on March 27 against Brother Elephants. In 49 games, Ramirez batted .352 with eight home runs and 43 RBIs, placing him in the top three in all categories. On June 19, 2013, Ramirez opted out of his contract with the Rhinos, stating that he wanted to be closer to his family.

Ramirez signed a minor league deal on July 3, 2013 with the Texas Rangers. He was assigned to the Round Rock Express of the Class AAA Pacific Coast League (PCL). After noticing a decrease in Ramirez’ bat speed, which resulted in a lack of power, the Rangers released Ramirez on August 13.

Ramirez signed a minor league deal with the Chicago Cubs on May 25, 2014, to serve as a player-coach for the Iowa Cubs, Chicago’s Class AAA affiliate in the PCL. Ramirez hit a two-run home run in his first Iowa home game at Principal Park on June 30, 2014. Cubs prospects Arismendy Alcántara and Javier Báez credited Ramirez for his help with their swings. Baez also viewed Ramirez as a good mentor because of how Ramirez comforted him after the loss of his uncle. On August 23, Ramirez sustained a knee injury. A week later, Iowa manager Marty Pevey announced that Ramirez was going to Arizona for an MRI. With only four games left in Iowa’s season, Pevey said that Ramirez was no longer going to coach and play for the team. Pevey said that he was uncertain about Ramirez plans for the next season, as he thought that Ramirez disliked the travel associated with Class AAA baseball.

On February 24, 2015, the Cubs announced that Ramirez was hired as a hitting consultant, and that he would split time between Chicago and AAA Iowa. In 2016, Ramirez was a hitting consultant for the Cubs.

On January 8, 2017, the Kōchi Fighting Dogs of the Japanese Shikoku Island League Plus independent league announced that they had reached an agreement with Ramirez to play for them in 2017. He left the team on August 17 to return to the United States for treatment of a knee injury.

in April 2020, Ramirez expressed interest in returning to the Chinese Professional Baseball League but was not offered a contract by a team. He later expressed interest in playing winter baseball for the New Zealand-based Auckland Tuatara of the Australian Baseball League if the leagues season is not cancelled due to Covid-19.

On August 29, 2020, Ramirez signed a one year deal with the Sydney Blue Sox to be a player-coach.