McDyess was selected with the second overall pick in the 1995 draft by the Los Angeles Clippers, and was traded to the Denver Nuggets before the season began, along with Randy Woods, for fellow forward Rodney Rogers and a mid-first-round pick that was later used to select Brent Barry. McDyess’s explosive leaping and power dunking ability allowed him to average 17.8 points and 8.8 rebounds per game over his first six seasons. In 1997, before his third year, McDyess was traded to the Phoenix Suns. He helped the Suns to a 56–26 record during his lone season in Phoenix.

McDyess was traded to the Knicks on June 26, 2002 in exchange for Marcus Camby, Mark Jackson and the draft rights to Nenê, the seventh overall pick in the 2002 NBA draft. McDyess began the 2002–03 season as a highly anticipated addition to the New York Knicks. But on October 8, 2002, with 1 minute 55 seconds left in an exhibition game against Phoenix, McDyess reinjured the knee while dunking a rebound. He would undergo another surgery four days later. In the 2003–04 season, McDyess was traded to the Phoenix Suns after just 18 games with the Knicks in an eight–player deal that brought Stephon Marbury to New York. He remained healthy while in Phoenix for the remainder of the 2003–04 season. That off-season, his knee was declared healthy and the Detroit Pistons signed him for the full mid-level exception.

On November 3, 2008, McDyess was traded to the Denver Nuggets, along with Chauncey Billups and Cheikh Samb, for Allen Iverson. His inclusion in the trade was for salary cap purposes only, and the Nuggets bought out his contract. He waited the league-mandated 30-day period before he could rejoin Detroit, then re-signed with the Pistons on December 9.

The San Antonio Spurs reached an agreement with McDyess on July 8, 2009 to a three-year deal worth the mid-level exception (up to $15 million). He spent the next two seasons with San Antonio as their starting Center, next to Tim Duncan.

On December 19, 2011, McDyess announced his retirement from the NBA.