McGwire was born in Pomona, California. His father was a dentist. He attended Damien High School in La Verne, California, where he played baseball, golf, and basketball. He was drafted by the Montreal Expos in the 1981 amateur draft but did not sign. He played college baseball at the University of Southern California (where he was a teammate of Randy Johnson and Jack Del Rio) under coach Rod Dedeaux.

McGwire was selected by the Athletics with the 10th overall selection in the 1984 MLB draft.

After three years at Southern California and a stint on the 1984 U.S. Olympic team, the Oakland Athletics drafted McGwire tenth overall in the 1984 Major League Baseball draft.

McGwire debuted in the major leagues in August 1986, hitting three home runs and nine runs batted in in 18 games.

Retaining his rookie status in 1987, McGwire took center stage in baseball with his home runs. He hit just four in the month of April, but followed in May with 15, and another nine in June. Before the All-Star break arrived, he totaled 33 HR and earned a spot on the American League (AL) All-Star team. On August 11, he broke Al Rosen’s AL rookie record of 37 home runs. Three days later, McGwire broke the major league record of 38, which Frank Robinson and Wally Berger jointly held. In September, McGwire hit nine more home runs while posting monthly personal bests of a .351 batting average, .419 on-base percentage (OBP) and 11 doubles (2B). With 49 HR and two games remaining in the regular season, he chose to sit them out with an opportunity for 50 home runs to be present for the birth of his first child. McGwire also totaled 118 runs batted in (RBI), .289 batting average, 97 runs scored, 28 doubles, a .618 slugging percentage and a .370 on-base percentage (OBP). McGwire’s 49 home runs as a rookie stood as a major league record until Aaron Judge hit 52 for the New York Yankees in 2017.

Not only did he lead the AL in home runs in 1987, but he also tied for the major league lead with Chicago Cubs right fielder Andre Dawson. McGwire also led the major leagues in SLG, finished second in the AL in adjusted on-base plus slugging percentage (OPS+, 164) total bases (344), third in RBI and on-base plus slugging (OPS, .987). He was thus a unanimous choice for the AL Rookie of the Year Award and finished sixth overall in the AL Most Valuable Player Award voting.

From 1988 to 1990, McGwire followed with 32, 33, and 39 home runs, respectively, becoming the first Major Leaguer to hit 30+ home runs in each of his first four full seasons. On July 3 and 4, 1988, he hit game-winning home runs in the 16th inning of both games. Through May 2009, McGwire was tied for third all-time with Joe DiMaggio in home runs over his first two calendar years in the major leagues (71), behind Chuck Klein (83) and Ryan Braun (79).

McGwire’s most famous home run with the A’s was likely his game-winning solo shot in the bottom of the ninth inning of Game 3 of the 1988 World Series against the Los Angeles Dodgers and former A’s closer Jay Howell. McGwire’s game-winner brought the A’s their only victory in the 1988 World Series, which they lost in five games; however, McGwire and his fellow Bash Brother, José Canseco, played a large part in the 1989 championship club that defeated the San Francisco Giants in the famous “Earthquake Series”.

Working diligently on his defense at first base, McGwire bristled at the notion that he was a one-dimensional player. He was generally regarded as a good fielder in his early years, even winning a Gold Glove Award in 1990 – the only one that New York Yankees legend Don Mattingly would not win between 1985 and 1994. In later years, his mobility decreased and, with it, his defense; however, McGwire’s batting averages after his rookie season plummeted to .260, .231, and .235 from 1988 to 1990. In 1991, he bottomed out with a .201 average and 22 homers. Manager Tony La Russa sat him out the final game of the season to avoid allowing his batting average to dip below .200. Despite the declining averages during this time of his career, his high bases on balls totals allowed him to maintain acceptable OBPs. In fact, when he hit .201, his OPS+ was 103, or just over league average.

The “new look” McGwire hit 42 homers and batted .268 in 1992, with an outstanding OPS+ of 175 (the highest of his career to that point), and put on a home run hitting show at the Home Run Derby during the 1992 All-Star break. His performance propelled the A’s to the American League West Division title in 1992, their fourth in five seasons. The A’s lost in the playoffs to the eventual World Series champion, the Toronto Blue Jays.

Foot injuries limited McGwire to a total of 74 games in 1993 and 1994, and just 9 home runs in each of the two seasons. He played just 104 games in 1995, but his proportional totals were much improved: 39 home runs in 317 at-bats. In 1996, McGwire belted a major league leading 52 homers in 423 at-bats. He also hit a career high .312 average, and led the league in both slugging percentage and on-base percentage.

On July 31, having already amassed 34 home runs to this point in the 1997 season, McGwire was traded from the Oakland Athletics to the St. Louis Cardinals for T. J. Mathews, Eric Ludwick and Blake Stein. Despite playing just two-thirds of the season in the American League, he finished ninth in home runs. In 51 games with the Cardinals to finish the 1997 season, McGwire compiled a .253 batting average, 24 home runs, and 42 RBI. Overall in 1997, McGwire led the majors with 58 home runs. He also finished third in the major leagues in slugging percentage (.646), fourth in OPS (1.039), fifth in OPS+ (170), tenth in RBI (123), and ninth in walks (101). He placed 16th in the NL MVP voting.

As the 1998 season progressed, it became clear that McGwire, Seattle Mariners outfielder Ken Griffey Jr., and Chicago Cubs outfielder Sammy Sosa were all on track to break Roger Maris’s single-season home run record. The race to break the record first attracted media attention as the home run leader changed often throughout the season. On August 19, Sosa hit his 48th home run to move ahead of McGwire; however, later that day McGwire hit his 48th and 49th home runs to regain the lead. On September 8, 1998, McGwire hit a pitch by the Cubs’ Steve Trachsel over the left field wall for his record-breaking 62nd home run, setting off massive celebrations at Busch Stadium. The fact that the game was against the Cubs meant that Sosa was able to congratulate McGwire personally on his achievement. Members of Maris’s family were also present at the game. The ball was freely, albeit controversially, given to McGwire in a ceremony on the field by the stadium worker who found it.

McGwire was honored with the inaugural Babe Ruth Home Run Award for leading Major League Baseball in home runs. Although McGwire had the prestige of the home run record, Sammy Sosa (who had fewer HR but more RBI and stolen bases) won the 1998 NL MVP award, as his contributions helped propel the Cubs to the playoffs (the Cardinals in 1998 finished third in the NL Central). Many credited the Sosa-McGwire home run chase in 1998 with “saving baseball”, by both bringing in new, younger fans and bringing back old fans soured by the 1994–95 Major League Baseball strike.

In a 1998 article by Associated Press writer Steve Wilstein, McGwire admitted to taking androstenedione, an over-the-counter muscle enhancement product that had already been banned by the World Anti-Doping Agency, the NFL, and the IOC; however, use of the substance was not prohibited by Major League Baseball at the time, and it was not federally classified as an anabolic steroid in the United States until 2004.

McGwire kept his high level of offensive production from 1998 going in 1999 while setting or extending several significant records. For the fourth consecutive season, he led MLB in home runs with 65. It was also his fourth consecutive season with at least 50 home runs, extending his own major league record. Sosa, who hit 63 home runs in 1999, again trailed McGwire. Thus, they became the first, and still only, players in major league history to hit 60 or more home runs in consecutive seasons. McGwire also set a record from 1998 to 1999 for home runs in a two-season period with 135. Further, he owned the highest four-season HR total, with 245 from 1996 to 1999. In 1999, he drove in an NL-leading 147 runs while only having 145 hits, the highest RBI-per-hit tally for a season in baseball history.

Known as one of the top sluggers of his era, McGwire ended his career with 583 home runs, which was fifth-most in history when he retired. When he hit his 500th career home run in 1999, he did so in 5,487 career at bats, the fewest in major league history. He led all MLB in home runs in five different seasons, including 1987 and each season from 1996 to 1999. Totaling 245 home runs from 1996−99, it was the highest four-season home run output in major league history. Further, in each of those four seasons, he exceeded 50 home runs, becoming the first player to do so. He was also the first player to hit 49 or more home runs five times, including his rookie-season record of 49 in 1987. With a career average of one home every 10.61 at-bats, he holds the MLB record for most home runs per at-bat by over a full at-bat more than second-place Babe Ruth (11.76).

In 1999, The Sporting News released a list of the 100 Greatest Baseball Players, ranking McGwire at number 91. The list had been compiled during the 1998 season and included statistics through the 1997 season. That year, he was elected to the Major League Baseball All-Century Team. In 2005, The Sporting News published an update of their list, and McGwire had been moved up to Number 84.

It was the last year of his contract, so there was speculation that McGwire would play for the Cardinals only for the remainder of the season, then seek a long-term deal, possibly in Southern California, where he still lived; however, McGwire signed a contract to stay in St. Louis. It is also believed that McGwire later encouraged Jim Edmonds, another Southern California resident who was traded to St. Louis, to forgo free agency and sign a contract with the Cardinals in 2000.

Statistically in 2000 and 2001, McGwire’s numbers declined relative to previous years as he struggled to avoid injury (32 HR in 89 games, and 29 HR in 97 games, respectively). He retired after the 2001 season.

McGwire finished the 1998 season with 70 home runs (including five in his last three games), four ahead of Sosa’s 66, a record that was broken three seasons later in 2001 by Barry Bonds with 73.

McGwire married Stephanie Slemer—a former pharmaceutical sales representative from the St. Louis area—in Las Vegas on April 20, 2002. On June 1, 2010, their triplet girls were born: Monet Rose, Marlo Rose, and Monroe Rose. They join brothers Max and Mason. They reside in a gated community in Shady Canyon, Irvine, California. Together they created the Mark McGwire Foundation for Children to support agencies that help children who have been sexually and physically abused come to terms with a difficult childhood. Mark has a son, Matthew (b. 1987), from a previous marriage (1984–1990, divorced) to Kathleen Hughes.

Jose Canseco released a book, Juiced: Wild Times, Rampant ‘Roids, Smash Hits & How Baseball Got Big, in 2005. In it, he wrote positively about steroids and made various claims—among them, that McGwire had used performance-enhancing drugs since the 1980s and that Canseco had personally injected him with them.

In 2005, McGwire and Canseco were among 11 baseball players and executives subpoenaed to testify at a congressional hearing on steroids. During his testimony on March 17, 2005, McGwire declined to answer questions under oath when he appeared before the House Government Reform Committee. In a tearful opening statement, McGwire said:

McGwire first became eligible for Hall of Fame voting in 2007. For election, a player needs to be listed on 75% of ballots cast; falling under 5% removes a player from future consideration. Between 2007 and 2010 McGwire’s performance held steady, receiving 128 votes (23.5%) in 2007, 128 votes (23.6%) in 2008, 118 votes (21.9%) in 2009, and 128 votes (23.7%) in 2010. The subsequent ballot in 2011 showed the first sub-20% total of 115 votes (19.8%), and McGwire’s total votes continued to decline (112 votes (19.5%) in 2012, 96 votes (16.9%) in 2013, 63 votes (11.0%) in 2014, and 55 votes (10.0%) in 2015) until he was finally eliminated after receiving only 54 votes (12.3%) in 2016.

After his playing career ended, McGwire demonstrated coaching ability, personally assisting players such as Matt Holliday, Bobby Crosby and Skip Schumaker before accepting an official role as hitting coach with an MLB team. On October 26, 2009, Tony La Russa, then manager of the Cardinals, confirmed that McGwire would become the club’s fifth hitting coach of his tenure with the Cardinals, replacing Hal McRae. McGwire received a standing ovation prior to the Cardinals home opener on April 12, 2010. In his three seasons as Cardinals hitting coach, they featured a prolific offense that led the National League in hitting and on-base percentage, and were second in runs.

A portion of Interstate 70 in Missouri in St. Louis and near Busch Stadium was named “Mark McGwire Highway” to honor his 70 home run achievement, along with his various good works for the city. In May 2010, St. Louis politicians succeeded in passing a state bill to change the name of “Mark McGwire Highway”, a 5-mile stretch of Interstate 70, to “Mark Twain Highway”.

On January 11, 2010, McGwire admitted to using steroids on and off for a decade and said, “I wish I had never touched steroids. It was foolish and it was a mistake. I truly apologize. Looking back, I wish I had never played during the steroid era.” He admitted using them in the 1989/90 offseason and then after he was injured in 1993. He admitted using them on occasion throughout the 1990s, including during the 1998 season. McGwire said that he used steroids to recover from injuries.

McGwire’s brother Dan McGwire was a quarterback for the Seattle Seahawks and Miami Dolphins of the NFL in the early 1990s, and was a first-round draft choice out of San Diego State University. He has another brother, Jay McGwire, a bodybuilder, who wrote a book in 2010 detailing their shared steroid use.

On June 11, 2013, McGwire was ejected for the first time as a coach during a bench-clearing brawl with the Arizona Diamondbacks. He was suspended for two games starting the next day.

On December 2, 2015, he was named the new bench coach for the San Diego Padres. He left the team after the 2018 season.

As of 2015, McGwire owned three of the four lowest single-season AB/HR ratios in MLB history, which covered his 1996, 1998 and 1999 seasons. They were actually the top three seasons in MLB history until Bonds broke his single-season HR record in 2001. McGwire’s 1997 season ranked 13th. Considered one of the slowest running players in the game, McGwire had the fewest career triples (six) of any player with 5,000 or more at-bats, and had just 12 stolen bases while being caught stealing eight times.