He has starred in the CBS television series Criminal Minds since 2007 as FBI Supervisory Special Agent David Rossi.

Mantegna also directed a highly lauded production of Mamet's Lakeboat, which enjoyed a successful theatrical run in Los Angeles.

In film and on television, Mantegna is best known for his roles in box office hits such as Three Amigos (1986), The Godfather Part III (1990), Forget Paris (1995), and Up Close and Personal (1996).

[3] His parents were Mary Ann (Novelli; 1916–2017), a shipping clerk from Acquaviva delle Fonti, Apulia, Italy,[4] and Joseph Henry Mantegna (1913–1971), an insurance salesman[5] from Calascibetta, Sicily,[6] who died in 1971 of tuberculosis.

He then attended Morton College and the Goodman School of Drama at the Art Institute of Chicago (now at DePaul University), leaving just before graduation in 1969.

He co-wrote Bleacher Bums, an award-winning play which was first performed at Chicago's Organic Theater Company, and was a member of its original cast.

[13] Mantegna won a Tony award for his portrayal of Richard Roma in David Mamet's play Glengarry Glen Ross.

Mantegna has played a wide range of roles, from the comic, as a jaded disc jockey in Airheads and an inept kidnapper from Baby's Day Out, to the dramatic, in roles such as Joey Zasa, a treacherous mobster in The Godfather Part III (1990) and an Emmy-nominated performance as singer Dean Martin in HBO's film The Rat Pack (1998).

Mantegna has a recurring role in the animated series The Simpsons as the voice of mob boss Anthony "Fat Tony" D'Amico.

Mantegna spoofed himself when he hosted Saturday Night Live for the 1990–1991 season in which he calmly began his monologue by saying he did not wish to be typecast from his gangster roles.

A disappointed little boy and his father leave, as they mistakenly believed the host would be Joe Montana (the football player) due to the similar names.

[16] On August 11, 2007, Mantegna signed on to replace departing star Mandy Patinkin on the CBS crime drama Criminal Minds.

Arlene owned a Chicago-themed restaurant in Burbank, California, named Taste Chicago, which closed on March 22, 2019, for personal reasons.

[29] Mantegna is a Chicago Cubs fan and has led the singing of "Take Me Out to the Ball Game" during the 7th inning stretch multiple times.