Malone played 21 seasons in the NBA. Before retiring from basketball, he was the last ABA participant to still be playing in the NBA.

Malone graduated from Petersburg High School to the ABA, being hired by the Utah Stars in 1974. He was one of the first basketball players to jump straight from high school into the professional leagues.

In two seasons in the ABA, Malone averaged 17.2 points and 13.9 rebounds per game. He played with the Stars and the Spirits of St. Louis.

After the ABA was merged with the NBA, Malone became a member of the Buffalo Braves, having been selected by the Portland Trail Blazers in the ABA dispersal draft but traded to the Braves after the draft. After a short period of time there, he was shipped to the Houston Rockets. He caused an immediate impact in Houston, helping make the franchise a respectable one and reaching the NBA Finals in 1981, where they lost in six games to Larry Bird and the Boston Celtics. Malone had been named the NBA's MVP two seasons earlier, in 1978-79.

After averaging 31 points per game in the 1981-82 season, Malone again won the MVP award. He was, however, traded to the Sixers over the course of the next summer. In Philadelphia, he teamed up with Julius Erving, Maurice Cheeks, and Bobby Jones, among others, to win his only NBA championship when the Sixers swept Magic Johnson and the Los Angeles Lakers during the 1983 NBA Finals. Said head coach Billy Cunningham, "The difference from last year was Moses" (the Lakers had beaten the Sixers in the 1982 NBA Finals). Malone was named MVP of the 1983 Finals, as well as league MVP for the third time. Before the 1983 playoffs began, Malone made the famous prediction "fo' fo' fo'"--as in "four, four, four"--claiming that the Sixers would sweep through the playoffs in the minimum 12 games. In fact, the Sixers went "fo' fi' fo'" (four, five, four), losing one game to the Milwaukee Bucks in the Eastern Conference Finals. Still, the Sixers' 12-1 record in the playoffs is the most dominant playoff run in NBA history.

Prior to the 1986-87 season, he was traded to the Bullets, but not before playing one season with legend in the making Charles Barkley. Once again, Malone helped his team reach a level of respectability with the Bullets, as they reached the NBA playoffs during the two seasons that Malone played with them. Malone then went on to star alongside Dominique Wilkins and Spud Webb on the Mike Fratello-coached Atlanta Hawks of 1988-89 and 1989-90.

Malone then went on to the Milwaukee Bucks after the 1990-91 season, remaining there until the summer of 1993.

Malone then rejoined the Sixers for a short period of time, participating with Manute Bol in what would be an injury plagued 1993-94 season. In 1994, he was sent to the Spurs, where he played the back-up center role behind superstar David Robinson. 1994-95 was his last season in the NBA. During the final game of his NBA career in a game against the Charlotte Hornets, he hit a buzzer-beating three-point shot from the opposing free throw line, eighty feet away from the goal. It was only the eighth three-pointer of his career. He played just 17 games for the Spurs, all in November and December 1994.

Malone wore several different jersey numbers in his career, among them No. 2 with the Sixers, Hawks and Spurs, No. 4 with the Bullets, No. 6 with the Bucks, No. 13 with the Spirits (ABA), No. 22 with the Stars (ABA), and No. 24 with the Rockets.

Malone became the first player in NBA history to earn five consecutive rebounding titles in five years after the 1984-1985 season, when he averaged 13 rebounds per game. During the latter years of his basketball career, he was also known for wearing thick glasses during games.

Malone helped his high school team to 50 wins in a row, and a number of state championships. He is second only to Karl Malone in overall (NBA & ABA) free throws made, with a total of 9,018 and to Wilt Chamberlain in overall (NBA & ABA) free throws attempted, with a total of 11,090.

Malone was named one of the NBA's 50 greatest players in 1997. In 2001, he was inducted into the Naismith Basketball Hall of Fame.

He did not foul out during his final 1,212 games - the longest streak of games played without a disqualification.