The 6-foot-11 Hughes played college basketball at the University of Wisconsin from 1971 to 1974, averaging 15 points and 11 rebounds as a senior. His identical twin, Kerry, also 6-11, was also a starter on the Badgers. Hughes was selected by the Buffalo Braves in the third round (ninth pick) of the 1974 NBA draft. He played professionally in Italy during the 1974–75 season. He spent the 1975–76 season with the New York Nets of the American Basketball Association (ABA), where he averaged eight points and nine rebounds and was named to the First Team ABA All-Rookie Team. The 1976 Nets team, which featured Julius Erving, Swen Nater, Larry Kenon and Brian Taylor, won the ABA championship.
Hughes spent two more seasons with the Nets after the franchise moved to the National Basketball Association (NBA). In July 1978, Hughes signed with the Denver Nuggets, where he played for two full seasons. Eight games into the 1980–81 NBA season, Hughes was traded to the Cleveland Cavaliers. He retired from the NBA at the end of the 1981 season, but continued to play professionally in Italy until 1989. During his ABA and NBA career, Hughes averaged 3.8 points and 5.6 rebounds per game, and had field goal and free throw percentages of 49.7% and 39.7%, respectively
In 2004, Hughes was diagnosed with prostate cancer, but the Clippers and Donald Sterling refused to cover the cost of his surgery. Several Clippers players, including Corey Maggette, Chris Kaman, Marko Jaric and Elton Brand, chipped in to pay for Hughes' treatment. It turned out that the cancer was more advanced than previously thought and about to metastasize. The cost of the surgery was estimated by Hughes to be at least $70,000.
On February 4, 2010, Hughes replaced Mike Dunleavy, Sr. as the head coach of the Los Angeles Clippers. On April 15, 2010, Hughes was released from his duties as interim head coach after going 8–25. On August 17, 2012, Hughes was named as an assistant coach for the Portland Trail Blazers.