Santoni was born in New York City on April 21, 1938. His family was of French (Corsican) and Spanish descent. He began his career in Off-Broadway theatre, writing the play Raisin’ Hell in the Son which premiered in 1962.

Santoni’s first significant film role was an uncredited appearance in the 1964 film The Pawnbroker (starring Rod Steiger), in which he played a junkie trying to sell a radio to the title character (using anti-Semitic slurs to no effect). His first leading role was as a young actor in Enter Laughing. He was cast into the role of delivery boy David Kolowitz after being scouted by Carl Reiner; the film was a semi-autobiographical story about the latter. Santoni went on to play Inspector “Chico” González in the 1971 film Dirty Harry. His character, who is a newcomer detective and college graduate in sociology, was initially dismissed by the title character as “a college boy”. He ultimately uttered the memorable phrase, “No wonder they call him Dirty Harry; [he] always gets the shit end of the stick”.

Santoni made guest appearances on television shows such as Barnaby Jones, Lou Grant, Hawaii Five-O, Hardcastle and McCormick, Hill Street Blues, The Odd Couple and Midnight Caller. In 1973, Santoni played a junior partner on Owen Marshall: Counselor at Law. His most notable later role was as “Poppie”, the bombastic, antiabortion, neurotic, and very unhygienic restaurateur in Seinfeld.

Santoni died on August 1, 2020, at a hospice in Los Angeles at the age of 82. He had several health issues during his last years, including cancer.