In 1989, he moved into the starting lineup when Oakley was traded to the New York Knicks for center Bill Cartwright. He immediately became the Bulls' main rebounder, and established himself as the Bulls' third scoring option after Jordan and Pippen, forming the one of league's best trios. He helped Chicago win three consecutive NBA championships (1990-91, 91-92, and 92-93). After Jordan retired following the 1992-93 season, he became the number two star behind Pippen, and helped the Bulls push the Knicks to seven games in the second-round playoff series before being defeated. In the offseason, however, he left the Bulls as a free agent, joining the young and rising Orlando Magic, led by young phenoms Shaquille O'Neal and Anfernee Hardaway. Grant helped the Magic reach the 1995 NBA Finals, where they were swept in four games by the more experienced Houston Rockets. Grant spent the next several seasons with the Magic, until he was traded to the Seattle SuperSonics in 1999. After the 1999-2000 season, he was involved in a three-way trade in which Glen Rice of the Los Angeles Lakers was sent to New York, Patrick Ewing of the Knicks was sent to Seattle, and Grant to the defending champion Lakers. He helped them win another championship in 2000-2001, but in the offseason decided to leave Los Angeles and sign back with the Magic. Grant was cut by the Magic after being called a 'cancer' to the team by then-coach Doc Rivers. He retired in the beginning of the 2002-2003 season, but briefly returned to the Lakers in the summer of 2003.

Grant was known as a strong defender and rebounder who could also provide a consistent source of points. He was easily recognizable by many NBA fans because of his trademark protective goggles.