As a high-school senior in San Antonio, Texas, O'Neal attracted the attention of college recruiters when his team won the state championship. He attended Louisiana State University (LSU), where he quickly established himself as one of the best players in the nation. He was named the consensus College Player of the Year in 1991. O'Neal left school and entered the NBA draft in 1992 and was taken with the first pick by the Orlando Magic. In 2000, however, he finished his studies and earned a degree from LSU.

Named NBA Rookie of the Year in 1992–93, O'Neal led the Magic to a 41–41 record, 20 wins better than the previous season. Two years later he won the scoring title and led Orlando to the finals against the Houston Rockets. After Houston's sweep of the Magic, O'Neal developed a reputation for losing big games. O'Neal's great size and strength—he stood 7 feet 1 inch (2.16 metres) tall and weighed 315 pounds (143 kg)—made him virtually impossible to stop on the offensive end of the court. He was, however, a poor free-throw shooter, and opponents adopted a strategy (known as “Hack-a-Shaq”) of intentionally fouling him, knowing that he was less likely to make free throws than to score a field goal.

O'Neal was a member of the so-called Dream Team, the U.S. Olympic basketball team that won the gold medal in 1996, the same year he joined the Los Angeles Lakers. Although O'Neal continued to dominate on offense, his teams also continued to disappoint in the play-offs. That changed in 1999–2000, when, under new Lakers coach Phil Jackson, O'Neal became the league's Most Valuable Player. At Jackson's urging, O'Neal became more of a team player, paying special attention to his defense, rebounding, and free-throw shooting. The result was that O'Neal led the Lakers to championships in 2001, 2002, and 2003.

In 2004 O'Neal was traded to the Miami Heat, where he teamed with the talented young guard Dwyane Wade to lead Miami to an NBA championship in 2006. Injuries limited O'Neal's production over the following seasons, and he was traded to the Phoenix Suns in February 2008.

O'Neal had limited success as a rapper and as an actor, starring in such feature films as Blue Chips (1994), Kazaam (1996), and Steel (1997).