The Chicago native began to develop an interest in theatrics while in high school. After completing his degree at the Goodman Theater School, Mantegna landed his first professional job playing Berger in a touring production of the musical "Hair". Returning home, he portrayed Judas in "Jesus Christ Superstar" before joining the Organic Theatre where he acted in several productions, including "The Wonderful Ice Cream Suit" and became friends with such future notables as Dennis Franz, Meshach Taylor and David Mamet. The latter has provided Mantegna with several fine roles on stage in films. Their theatrical collaboration began with the two-hander "A Life in the Theater" (1976) and has included the actor's award-winning turn as the foul-mouthed real estate broker Ricky Roma in "Glengarry Glen Ross" (1984) and the sleazy Hollywood producer Bobby Gould in "Speed-the-Plow" (1988). On the big screen under Mamet's direction, Mantegna has essayed a smooth con man in "House of Games" (1987), a Mafioso who offers a final fling to a shoeshine man (Don Ameche) who has confessed to a murder he didn't commit in "Things Changes" (1988) and a troubled detective investigating the murder of an elderly Jewish woman in "Homicide" (1991). In each case, the actor brought his expertise and understanding to the writer's work, delivering finely-tuned characterizations. Many critics cited Mantegna as the pre-eminent interpreter of Mamet's work. Despite this, "Homicide" marks their last big screen collaboration to date.

While David Mamet has provided three-dimensional characters for Mantegna, Hollywood has seemingly not known what to do this versatile actor. All too often he has been cast as heavies or gangsters which he has played well (notably, 1990's "The Godfather, Part III" and his Emmy-nominated performance in the 1997 CBS miniseries "Mario Puzo's The Last Don"). Other filmmakers have tapped into different sides of the actor. Woody Allen has cast him as the sweet, almost too-good-to-be-true swains of the heroines in "Alice" (1990) and "Celebrity" (1998) while Steve Zaillian saw him as an average father of a chess prodigy who puts too much pressure on his son in the underrated "Searching for Bobby Fischer" (1993). In Barry Levinson's "Bugsy" (1991), Mantegna offered a delightful turn as Hollywood tough guy George Raft, actor and pal to real-life gangsters like Bugsy Siegel (Warren Beatty); the pair reteamed for Levinson's semi-autobiographical underrated "Liberty Heights" (1999), with Mantegna shining as Nate Kurtzman, father to Levinson's on-screen alter ago Ben (Ben Harper). Unfortunately, most of Mategna's subsequent big screen roles in the late 1990s and early 2000s have failed to capitalize on his distinctive talents.

The small screen has also offered Mantegna a wider range of characters. He offered a very fine performance as an emergency room physician coping with stress in "State of Emergency" (HBO, 1994) and proved effective as a Holocaust survivor in "A Call to Remember" (Starz!, 1997). In 1998, he caught some flack for his impersonation of Dean Martin in the HBO biopic "The Rat Pack" (those close to the figures portrayed were vocal in their objections while critics were divided in their reactions). Mantegna received a warmer critical reception when he assumed the role of Spenser, the Boston-based private investigator hero of a series of mysteries by Robert Parker, in "Small Vices" (A&E, 1999), the first in a series of telefilms including "Thin Air" (2000) and "Walking Shadow" (2001). He also saw his 1979 play "Bleacher Bums" turned into a 2002 TV movie.