He originally arranged to get the physician; he attended Georgetown University on a USAID scholarship. Georgetown basketball coach John Thompson convinced him to play basketball. He became an first-class college center, continuing Georgetown's tradition of producing great large men. He was the celebrated shot blocker at Georgetown, setting the team record of dozen blocked shots around one game. Building on the shot-blocking power of Mutombo & mate Alonzo Mourning, Georgetown fans created a "Rejection Row" division under a basket, adding the large silhouette of an outstretched hand to a banner for both shot blocked in the period of the game. When at Georgetown, Mutombo's international background & interests stood out. Prefer several more Inland northwest-region university student, he served as a summertime houseman, another time for the U.S. Congress and once for the World Bank. He was likewise easily known in campus for his patented sentence "Who wants to sex Mutombo?" which normally generated the jolly full response from either the coeds, world health organization had the rise away from seeing a super big Seven' Deuce" man with a deep Cookie Monster-like voice shouting the phrase whenever entering the Georgetown bars and clubs.

Selected fourth overall by the Denver Nuggets in the 1991 NBA Draft, Mutombo's impact was immediate. As a rookie, he was selected for the All-Star team by averaging 16.6 points, 12.3 rebounds, and nearly three blocks per game. A cornerstone in the Nuggets' frontcourt, Dikembe became one of the league's best defensive players, regularly putting up big rebound and block numbers for five years with the club while averaging 11 or so points a game. The team lacked other great players to team up with him, however, and at its best won only 42 games, in his rookie season. However, that season, it pulled off a major playoff upset by stunning the top-seeded Seattle SuperSonics in the first round, the first eighth seed to win an NBA playoff series. Mutombo's defensive presence was the key to this upset victory. His total of 31 blocks remains a record for a five-game series. The following season, he received the NBA Defensive Player of the Year Award.

After the 1995-96 season, Mutombo's contract with the Nuggets expired, and he signed a free agent contract with the Atlanta Hawks. Mutombo continued to put up excellent defensive numbers with his new team. Joining the Hawks made him more noticeable, helping him win two more Defensive Player of the Year awards and several All-Defensive Team selections. He also became fairly well known for his signature finger waggle, which he would point at a player's direction after he had blocked that player's shot. During the lockout-shortened 1998-99, he was the NBA's IBM Award winner, a player of the year award determined by a computerized formula.

The Hawks fell from grace afterwards, and Mutombo was traded to the Philadelphia 76ers in February 2001. He earned his fourth Defensive Player of the Year award that season and was in the prime of his career. That season he also earned a trip to the NBA Finals, where the 76ers lost to the Los Angeles Lakers four games to one. Following another stellar defensive year in 2001-02, the Sixers dealt him to the New Jersey Nets, who were looking for a more physical big man to compete with Shaquille O'Neal and Tim Duncan, two of the best big men in the league who also led championship-caliber teams in the West. Unfortunately, Mutombo spent most of that season with a nagging injury that limited him to just 24 games. He was generally unable to play in the playoffs, typically serving as a twelfth man during the Nets' second consecutive Finals run.

In October 2003, the Nets bought out the remainder of his contract and subsequently waived him. He signed a two-year deal with the New York Knicks a few days later. The Knicks later traded him to the Chicago Bulls in a package for Jamal Crawford. He never played a game for the Bulls and they dealt him to the Houston Rockets in the 2004 offseason.

A well-known humanitarian, Mutombo started the Dikembe Mutombo Foundation to improve living conditions in his native Zaire, now the Democratic Republic of Congo, in 1997. His efforts earned him the NBA's humanitarian award in 2001. In the same year, ground was broken for a hospital in his hometown, the Congolese capital of Kinshasa. When it opened in 2004, it became the first modern medical facility to be built in that area in nearly 40 years. He personally donated $3.5 million toward the hospital's construction.

Mutombo is fluent in seven languages: English, French, Spanish, Portuguese, and three central African dialects. Known for his engaging personality, Mutombo was selected to an NBA All-Interview team in 2002. When Georgetown was playing Duke University in the 1989 NCAA tournament, many Georgetown fans enjoyed poking fun at the occasionally pretentious Duke fans by noting that he spoke more languages than the entire Duke team and coaches.