Santoni's first leading role was as the young actor in Carl Reiner's Enter Laughing. Other film roles included Inspector "Chico" González in 1971's Dirty Harry, prison official Ramon Herrera in the 1983 drama Bad Boys and detective Tony Gonzales in the 1986 action film Cobra. He also 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.