Grifasi broke into feature films as the bandleader in Michael Cimino's "The Deerhunter" (1979) and worked steadily in supporting roles, often as a character who proves not to be as tough as he pretends. Although much of his early feature film work was in fluff, Grifasi was gradually cast in prestige films, including a turn as a detective in Robert Benton's "Still of the Night" (1979), as a cop partnered with Brian Dennehy in "F/X" (1986) and as a miner in John Sayles' union drama "Matewan" (1987). Perhaps one of his more memorable turns was as the confused hotel desk clerk in "Big Business" (1988). In Alan J Pakula's legal thriller "Presumed Innocent" (1990), Grifasi was Tommy Molto, a sleazy lawyer determined to prove Harrison Ford guilty of murder, while in Sayles' "City of Joy" (1992), he appeared as Tony LoBianco's brother. He appeared in small roles in Garry Marshall's 1988 film "Beaches" (as Otto Titsling), Jeremiah Chechik's "Benny and Joon" (1993), Oliver Stone's "Natural Born Killers" and the Coen Brothers' "The Hudsucker Proxy" (both 1994). In 1995, he was featured in four films: as the Man in the Top Hat in Chechik's "Tall Tale: The Unbelievable Adventures of Pecos Bill"; as the hapless guard trapped by Two-Face (Tommy Lee Jones) and saved by Batman (Val Kilmer) in the opening sequence of Joel Schumacher's "Batman Forever"; as Uncle Joe in James Foley's "Two Bits"; and as Riley in Joseph Ruben's "The Money Train". He appeared as a barfly in "Heavy" (1996).

Grifasi's TV work began in 1974 with an episode of "Dr Simon Locke" (aka "Police Surgeon"), a syndicated series. In 1990, he starred in the short-lived CBS series "WIOU" as Tony Pro, a hard-working press agent. He is remembered as Joe Evans, the steady bartender in the CBS miniseries "Sinatra" (1992).