Keitel studied under both Stella Adler and Lee Strasberg, eventually landing roles in some off-Broadway productions. During this time, Keitel met another struggling filmmaker named Martin Scorsese and gained a part in Scorsese's student production, Who's That Knocking at My Door. Since then, Scorsese and Keitel have worked together on numerous projects. Keitel had the starring role in Scorsese's Mean Streets but this proved to be Robert De Niro's breakthrough film. He later appeared with De Niro in Taxi Driver, playing the role of a pimp.

Originally, Keitel was to have played the role of Captain Willard in Francis Ford Coppola's Apocalypse Now; however, he was fired early in the production and replaced by Martin Sheen. After this, it was many years before he would be able to get anything other than minor roles. At the end of the 1970s, Keitel was mostly working in European films for directors such as Ridley Scott, usually in sinister character parts.

Throughout the 1980s