[1][2] He rose to prominence during the New Hollywood movement, and has held a long-running association with director Martin Scorsese, starring in six of his films: Who's That Knocking at My Door (1967), Mean Streets (1973), Alice Doesn't Live Here Anymore (1974), Taxi Driver (1976), The Last Temptation of Christ (1988), and The Irishman (2019).

[4] Keitel has starred in several other films, including Blue Collar (1978), Thelma & Louise (1991), Reservoir Dogs (1992), Bad Lieutenant (1992), Imaginary Crimes (1994), Pulp Fiction (1994), From Dusk till Dawn (1996), Cop Land (1997), Holy Smoke!

Additionally, Keitel has starred in three films directed by Wes Anderson: Moonrise Kingdom (2012), The Grand Budapest Hotel (2014), and Isle of Dogs (2018).

[8] Keitel studied under both Stella Adler and Lee Strasberg and at the HB Studio,[11] eventually landing roles in some Off-Broadway productions.

[8] In 1977 and 1978, Keitel starred in the directorial debuts of Paul Schrader (Blue Collar, co-starring Richard Pryor and Yaphet Kotto), Ridley Scott (The Duellists, co-starring Keith Carradine), and James Toback (Fingers, in which Keitel played a street hood with aspirations of being a pianist – a role Toback wrote for Robert De Niro to play).

Keitel played a corrupt police officer in the 1983 thriller Copkiller (co-starring musician John Lydon), before taking a supporting role in the romantic drama Falling in Love (1984), starring Robert De Niro and Meryl Streep.

Between 1985 and 1988, he was one of the busiest character actors around, appearing in 16 films and telefilms,[13] including Brian De Palma's mobster comedy Wise Guys (1986), starring Danny DeVito and Joe Piscopo, and as Judas in Martin Scorsese's controversial The Last Temptation of Christ (1988).

[8] In 2008, Keitel was cast in the role of Detective Gene Hunt in ABC's short-lived US remake of the successful British time-travel police drama series Life on Mars.

[18] Between 2014 and early 2020, he reprised his role of Winston Wolf from Pulp Fiction as part of a £40 million television advertising campaign for British insurance company Direct Line.

[21] In 2022, Keitel starred in Steven Brand's noir thriller Joe Baby alongside Dichen Lachman, Willa Fitzgerald and Ron Perlman.

[22] Keitel has recently collaborated with Wes Anderson acting in minor roles in his films Moonrise Kingdom (2012), The Grand Budapest Hotel (2014), and Isle of Dogs (2018).

He reunited with Martin Scorsese after 30 years appearing as Philadelphia crime family acting boss Angelo Bruno in his gangster movie The Irishman (2019) alongside Robert De Niro and Joe Pesci.