Matuszak was born in Oak Creek, Wisconsin, in 1950 to Audrey and Marvin Matuszak (not the same Marvin Matuszak who was a defensive lineman in the NFL and AFL). He was always big for his age, which became an advantage as a defensive lineman in football. When he eventually turned pro, he stood 6 feet 8 inches (2.03 m) and weighed over 280 pounds (127 kilograms). He attended the University of Tampa where he was the star of their football team.
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, but played a total of seven plays before a restraining order that was served to him during a game that barred 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 found himself 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 following spending the entire 1982 season on injured reserve.
His football career was often overshadowed by his even more famous (or infamous) partying and seemingly endless 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 (Matt Millen told reporters on several occasions how he disliked Matuszak and found him to be phony) and not being one of Al Davis's favorite post-retirement players, and after an ugly incident where Matuszak violently assaulted assistant coach Terry Robiskie due to Matuszak hearing a false rumor that the team was going to trade away star tight end Todd Christensen, he was banned from ever setting foot in the Raiders' HQ again.
John Matuszak died as a result of an accidental overdose of a prescription drug, according to the findings of the Los Angeles County Coroner's Office. A report listed the cause of death as acute propoxyphene intoxication. Propoxyphene is the generic name for the prescription pain medicine known as Darvocet. The report added that a small amount of cocaine metabolite was found in Matuszak's blood, but was not considered to have contributed to his death. The report said that hypertrophic cardiomyopathy, an enlarged heart, and bronchopneumonia had been contributing factors in the death. Dambacher said Matuszak had been experiencing back pain, a problem that had caused his retirement from football after the 1981 season.