Cruz was born on July 1, 1980 in Las Matas de Santa Cruz, Dominican Republic. His father, Nelson Cruz Sr., also played professional baseball in the Dominican Republic. Both his parents are successful professors and they raised Cruz and his two sisters, Nelsy and Olga, in a well-to-do Dominican neighborhood. Growing up, Cruz’s passion was for basketball, not baseball. His idol was Michael Jordan and as a teenager Cruz played for the Dominican Republic Junior National Basketball Team. He attended the high school where his father taught history. In addition to playing sports, Cruz worked as a mechanic’s helper with his uncle at a tractor factory. He also shined shoes and learned how to repair them. In September 2012, he donated $20,000 to help buy a firetruck for Las Matas de Santa Cruz, enlisting AMR’s help in also donating two ambulances.

Cruz was initially signed as a non-drafted free agent by the New York Mets, and played for three years in the Dominican Summer League. On August 30, 2000, the Mets traded him to the Oakland Athletics for shortstop Jorge Velandia, as starting shortstop Rey Ordóñez was out with a broken arm, and Melvin Mora, Mike Bordick, and Kurt Abbott proved unable to fill in. Cruz spent four years in Oakland’s minor league system then was traded on December 16, 2004 to the Milwaukee Brewers for infielder Keith Ginter.

Cruz spent the 2005 and 2006 seasons in the Brewers organization, primarily with the Double-A Huntsville Stars, Triple-A Nashville Sounds. He made his major league debut with the Brewers on September 17, 2005 as a late inning defensive replacement at right field wearing #8 against the Houston Astros. He had one hit in five at-bats for the Brewers in limited action. His only hit was a double off Aaron Harang of the Cincinnati Reds on September 28.

On July 28, 2006, the Brewers sent Cruz and outfielder Carlos Lee to the Texas Rangers in exchange for Laynce Nix, Kevin Mench, Francisco Cordero and minor league pitcher Julian Cordero. Cruz would wear #17 during his time with Texas. He hit his first home run on July 31 against Willie Eyre of the Twins. On August 16, Cruz hit the first grand slam of his career off of Kevin Gregg of the Angels. On September 4, 2006, against the Athletics, he hit an inside-the-park home run in which his bat broke on impact. In spring training for the 2007 season, Cruz got off to a rough start, but finished strong by hitting three home runs in the final week, including a walk-off home run in the final game of spring training.

On August 25, 2008, the Rangers purchased Cruz’s contract from the Triple-A Oklahoma RedHawks. With the RedHawks Cruz had a .341 batting average and had 37 home runs and 100 runs batted in (RBI); for his efforts with the RedHawks, Cruz won the 2008 Pacific Coast League MVP award.

In July 2009, Cruz was selected as an All-Star as a replacement for injured Torii Hunter. He also participated in the 2009 Home Run Derby, finishing second to Brewers first baseman Prince Fielder.

Cruz and Solani Genao were married on December 25, 2009. They have a daughter, Giada, and a son, Nelson Jr. The family resides in New York City during the offseason.

He and teammate Ian Kinsler each hit three home runs in the 2010 AL Division Series against the Tampa Bay Rays, marking only the second time in Major League history that two teammates each hit three homers in a postseason series of five games or fewer (joining Babe Ruth and Lou Gehrig, who did it in the 1928 World Series). In Game 5 of the 2010 World Series vs. the San Francisco Giants, Cruz hit a home run off of Tim Lincecum in the 7th inning. It was around this time that Cruz began to refer to his baseball bat as a “boomstick.”

In 2011, Cruz and Ian Kinsler became the first two teammates in major league history to homer in each of the first three games in a season, joining Dean Palmer (1992) as the only Texas ballplayers to ever homer in the first three games of the season. Also, in his very next game, Cruz became the third player ever to homer in each of the first four games of the season, joining Willie Mays and Mark McGwire.

In 2011, Cruz batted .263 with 29 home runs. He led AL right fielders in range factor for the third straight year (2.29). On October 10, 2011, Cruz hit a walk-off grand slam in Game 2 of the ALCS versus the Detroit Tigers. He became the first player in baseball history to hit a walk-off grand slam in a postseason game.

In January 2013, Cruz was linked to buying performance-enhancing drugs from a clinic based in Miami. On August 5, 2013, Cruz was suspended 50 games by Major League Baseball for his involvement in the Biogenesis scandal.

On February 24, 2014, Cruz signed a one-year, $8 million, contract with the Baltimore Orioles. Cruz wore #23 with the Orioles and continued wearing 23 in his stops with the Seattle Mariners and the Minnesota Twins.

On July 5, Cruz had his first career 5-hit game, with two singles, two doubles, and a home run, falling a triple shy of the cycle (he was tagged out just short of third base), against the Red Sox. He was elected into his third MLB All-Star Game, as a designated hitter, for the American League. On September 7, 2014, in a game against the Tampa Bay Rays, Cruz went 4-for-5 with two home runs and 7 RBIs, including his 100th RBI of the season. His previous season high in RBIs had been 90, set in 2012. Cruz drove in all 7 runs the Orioles scored. In 159 games played in 2014, Cruz had an MLB-leading 40 home runs along with a .271 batting average, 32 doubles, and 108 RBI.

On December 4, 2014, Cruz signed a four-year contract with the Seattle Mariners worth $57 million.

Cruz was named the starting DH for the 2015 American League All-Star team, marking the 4th time (3rd consecutive) that he was named an All-Star. He went on to have arguably the best season of his career in 2015, hitting .302 with a career-high 44 home runs and 93 RBIs. He hit the third-longest home run in MLB in 2015, at 483 feet. He also won his first career Silver Slugger Award, and finished 6th in the American League MVP voting.

In 2016, Cruz batted .287 with 43 home runs and 104 RBIs. He was not selected as an All-Star, but did finish 15th in the American League MVP voting. His batted balls had the highest average exit velocity of the season in the major leagues, at 94.4 miles per hour. He also hit the second-longest home run in MLB in 2016, at 493 feet.

Cruz was selected as an All-Star in 2017 for the fifth time in his career. On July 7, he hit his 300th career home run in a Mariners win over the Oakland Athletics. Cruz led the AL in RBIs with 119, and led the Mariners in home runs (39), runs scored (91), extra base hits (67), walks (70), OPS (.924), on-base percentage (.375), and slugging percentage (.549). He won the Edgar Martínez Award, also known as the Outstanding Designated Hitter Award.

After the 2018 season, Cruz became an American citizen.

On January 2, 2019, Cruz signed a one-year contract with the Minnesota Twins worth $14.3 million. The contract also included a $12 million team option for the 2020 season.

On September 22, 2019, Cruz hit his 400th career home run and 40th home run of the season versus the Kansas City Royals. He batted .311/.392/.639 with 41 home runs and 108 RBI in 120 games on the season. He produced the highest hard-contact percentage of all major league batters, at 52.5%. He was the fifth-oldest player in the American League. For first time in his MLB career, he did not play in the field; he played in 114 games as a DH and another six as a pinch hitter. His 1.031 OPS matched the club record, and his home run and RBI totals set club records at DH. He ranked second in the AL in OPS and SLG, tied for third in home runs, placed sixth in batting, and seventh in RBI. He followed Hank Aaron and Barry Bonds as tne only players to hit 40 home runs in their age-39 season or after. These accomplishments helped net Cruz his third career Silver Slugger Award.

For his efforts assisting the community, Cruz was selected as the 2020 Marvin Miller Man of the Year by the MLB Players Association, as that player whom his peers deem earned “most respect based on his leadership on the field and in the community,” notably in his hometown of Las Matas de Santa Cruz. He also was the ESPYs Muhammed Ali Sports Humanitarian Award winner in 2020. Cruz donated a police station, a fire station, replaced an aging ambulance and spearheaded a $400,000 donation drive to help alleviate food shortgages induced by the COVID-19 pandemic. His leadership inspired his teammates to assist in their own communities.