In his prime, he was perhaps the Babe Ruth of the 1990s. Like Ruth, he was a big man, and a prolific home run hitter; he hit the ball out of the park once in every 9.42 at bats, beating out Ruth for the highest home run ratio in major-league history. Like Ruth, he had begun as an outstanding pitcher. And like Ruth, he was a superb low ball hitter who learned to golf the ball for titanic home runs, balls that sometimes cleared the fences with 100 feet (30 m) to spare. Because of this uncanny ability to hit the long ball, teammates called him "Colossus". Other nicknames of his included "Big Mac" and "The Reptile".

McGwire ended his career with 583 home runs, which was then 5th-most in history. He hit 50 or more home runs four seasons in a row (1996-1999), and led Major League Baseball in homers all four seasons. He also shared the MLB lead in home runs in 1987, his rookie year, when he set the Major League record for home runs by a rookie with 49. Although McGwire led the majors in homers five times, he was a league leader only four times. In 1997, he did not lead either league in homers, as he was traded from the Oakland Athletics to the St. Louis Cardinals in midseason. It was widely believed that McGwire, in the last year of his contract, would play for the Cardinals only for the remainder of the season, then seek a long-term deal, possibly in Southern California where he lives. However, McGwire instantly fell in love with the Cardinal fans (considered among the most knowledgeable and loyal in baseball) and signed a long-term deal to stay in St. Louis instead. (It is also believed that McGwire encouraged Jim Edmonds, another Southern California resident who was traded to St. Louis, to sign his current contract with the Cardinals.)

In 1998, the year when McGwire and Sammy Sosa spent much of the season chasing the single-season home run record of Roger Maris, the two shared Sports Illustrated magazine's "Sportsmen of the Year" award. It is worth noting that McGwire admitted to administering Androstenedione, an androgenic steroid, during the same year, although at the time it was not tested for by the MLB and was not against the rules at that time.

McGwire worked hard on his defense at first base, and resisted being seen as a one-dimensional player. McGwire also had a sense of baseball history that is rare among modern players. He graciously involved the family of Roger Maris when he broke Maris's single season home run record on September 8, 1998. He finished the season with 70 homers, a record that has since been broken by Barry Bonds. (Appropriately, a section of Interstate 70 through St. Louis is named the Mark McGwire Highway.)

McGwire began his career with the Oakland A's and played there until 1997, when he concluded his career with a few years with the St. Louis Cardinals. He won the World Series just once, with the Oakland A's in 1989. Perhaps Mark McGwire's most famous home run as an Oakland Athletic was in Game 3 of the 1988 World Series against the Los Angeles Dodgers. McGwire's game winning solo homer off of Jay Howell in the bottom of the 9th inning ultimately became the only game that the A's won in the 1988 World Series.

McGwire won a silver medal with the USA amateur baseball team in the 1984 Summer Olympics; that team was coached by Rod Dedeaux, who had also been his college coach at the University of Southern California.Since he retired, McGwire has kept a low profile. His admission that he used the supplement androstenedione has led to speculation that he also took steroids. Although McGwire had repeatedly denied using illegal performance-enhancing drugs, he refused to do so under oath when he appeared before the House Government Reform Committee on March 17, 2005. As McGwire said in his opening statement, "Asking me or any other player to answer questions about who took steroids in front of television cameras will not solve the problem. If a player answers 'No,' he simply will not be believed; if he answers 'Yes,' he risks public scorn and endless government investigations." When asked if he was asserting his Fifth Amendment right not to incriminate himself, McGwire said: "I'm not here to talk about the past. I'm here to be positive about this subject."

In perhaps a touch of subtle irony, he married former pharmaceutical sales representative Stephanie Slemer in Las Vegas on April 20, 2002. They have a son, Max. McGwire has a son, Matthew, by his first wife Kathy. His brother Dan McGwire was a quarterback for the Seattle Seahawks in the early 1990's.

He also created the Mark McGwire Foundation for Children to support agencies that work with children who have been sexually and physically abused.