Faison was born in Newport News, Virginia, the son of Carmena (née Gantt) and Edgar Faison. He studied drama at Illinois Wesleyan University in Bloomington, Illinois, where he joined Theta Chi fraternity. He went on to obtain a Master of Fine Arts degree from New York University's Tisch School of the Arts, graduating in 1974.Frankie has been married to Samantha Jupiter Faison since 2017.
Faison started his acting career in 1974 in the New York Shakespeare Festival production of King Lear, with James Earl Jones in the title role. Faison later appeared opposite Jones in the Broadway premiere of Fences, for which he received a nomination for a Tony Award for Best Featured Actor in a Play. Faison's next role came in TV, in the short-lived series Hot Hero Sandwich in 1979. Faison did not make it to the big screen until 1980, when he appeared in Permanent Vacation as "Man in Lobby". A string of small roles followed until 1986, when he played the part of Lt. Fisk in Manhunter. Also that year, he appeared in the comedy The Money Pit, as an unruly construction worker, and in the Stephen King film Maximum Overdrive. In 1988, he appeared alongside Eddie Murphy and James Earl Jones in Coming to America in the role of a landlord, and won a minor role in the 1989 Spike Lee film Do the Right Thing. Faison also appeared in 1996's The Rich Man's Wife as Detective Ron Lewis. He also appeared in the 1999 remake of The Thomas Crown Affair as Detective Paretti. Faison is notable for being the most frequent actor to appear in adaptations of Thomas Harris' Hannibal books: along with Manhunter, he also appeared as Lecter's jailer Barney in The Silence of the Lambs, the sequel Hannibal, and the prequel Red Dragon.
During the 1990–1991 season, he starred in the Fox situation comedy True Colors with Stephanie Faracy and Nancy Walker about an interracial couple. He was replaced by Cleavon Little for the second season of the program. In 1991, Faison again appeared alongside Hopkins in the film Freejack, which also starred Mick Jagger and Maximum Overdrive co-star Emilio Estevez. In 1998, he was a regular on the science-fiction TV show Prey. In 1992, he played the patriarch Bailey in the Cheryl West play Before It Hits Home. In the 2003 film Gods and Generals, Faison played the role of Jim Lewis, a freed slave, who shares his religious faith and optimism with CSA General Thomas J. "Stonewall" Jackson as the general's personal cook. In 2004, he starred as JoJo Anderson in The Cookout and appeared in White Chicks. Faison had a starring role as the Baltimore City Police Commissioner Ervin Burrell on the HBO drama The Wire.

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