Matuszak, drafted by the Houston Oilers of the NFL, was the first draft pick of 1973. In addition to his contract with the Oilers, he joined the Houston Texans of the World Football League, playing a total of seven plays before a restraining order was served to him during a game, barring him from playing for two teams at the same time. Matuszak said he had no plans to play in that game but requested to play after seeing 25 or so men looking for him on the sidelines. He didn't know what was happening at the time and wanted to avoid confrontation. The Oilers, displeased that he tried joining the WFL, traded him to the Kansas City Chiefs, where he played until 1975. Then he signed with the Raiders in 1976 after being released in pre-season by the Washington Redskins. He helped the Raiders win two Super Bowls (XI and XV) before retiring after spending the entire 1982 season on injured reserve.

Matuszak acted professionally in the 1980s, making appearances in feature films and on television, often portraying football players or gentle giants. His first major role was in the 1979 movie North Dallas Forty as a football player. He appeared in the movies Caveman, The Ice Pirates, One Man Force, and One Crazy Summer, but is frequently remembered as deformed captive Sloth in The Goonies, the make-up for which took five hours to apply. Matuszak's character Sloth wears an Oakland Raiders shirt in some scenes. He had numerous guest appearances in TV shows such as Perfect Strangers, M*A*S*H, The Dukes of Hazzard, Hunter, Silver Spoons, The A-Team, 1st & Ten, Miami Vice and Cheers.

Matuszak died on June 17, 1989, as a result of acute propoxyphene intoxication, an accidental overdose of the prescription drug Darvocet, according to the findings of the Los Angeles County Coroner's Office. The report also said that hypertrophic cardiomyopathy (an enlarged heart) and bronchopneumonia had been contributing factors in his death. There were also traces of cocaine found in his blood stream. He was 38 years old.

His football career was often overshadowed by his even more famous use of drugs. In his autobiography, he stated that he took many painkillers as well as other narcotics while playing professional football. Because of this, an article written for Sports Illustrated's website in January 2005 named him one of the top five all-time "bad boys" of the NFL. Although his performances made him one of the best Raider defenders of all time, his volatile actions contributed to him not being popular with teammates and not being in Al Davis's favor.