Manley was drafted in the fifth round (119th overall) of the 1981 NFL Draft by the Washington Redskins, where he played for nine seasons. During his career with the Redskins, Manley won two Super Bowl titles and was a Pro Bowler in 1986 when he recorded a Redskins single season record 18.5 sacks. He then played for the Phoenix Cardinals and the Tampa Bay Buccaneers; while with the Bucs, he often hung out with Tampa 1st round draft pick Keith McCants, who would later battle similar drug problems. In 1989, Manley failed his third drug test and was banned from the NFL for life, with an opportunity to apply for reinstatement after one year. However, after he failed his fourth drug test, he was permanently banned from the National Football League for life on December 12, 1991.
Officially, Manley had 97.5 quarterback sacks in his career. His total rises to 103.5 when the six sacks he had his rookie year of 1981, when sacks were not yet an official statistic, are included. After his career in the United States ended, he revealed that he was functionally illiterate, despite having studied at Oklahoma State University for four years.
Manley also played two seasons in the Canadian Football League with the Ottawa Rough Riders in 1992 and 1993 after being banned from the NFL. In 1995, Manley was convicted of cocaine possession and was sentenced to four years in prison, of which he served two.
In 2002, he was selected as one of the 70 Greatest Redskins of All Time and is a member of the Washington Redskins Ring of Fame.
Manley underwent 10½ hours of brain surgery June 21, 2006, to treat a Colloid cyst, and is experiencing minor, isolated memory loss. He first learned about the cyst in 1986, when after an all-night drug spree, he collapsed in a Georgetown department store. His prognosis is for a relatively full recovery, although doctors have said that memory loss is a common side effect of the operation. Manley lives in suburban Washington with his wife and family.
In an article by Taylor Branch entitled "The Shame of College Sports", prior to the U.S. Senate Subcommittee on Education, Arts, and Humanities in 1989, Manley was famously quoted as saying that he had been functionally illiterate in college.