He was noted for playing Poppie on the television sitcom Seinfeld, Tony Gonzales in Cobra, and Chico González in Dirty Harry.

[7] 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.

[9] Santoni again collaborated with Reiner in the comedic homage to film noir Dead Men Don't Wear Plaid (1982).

[7] He was described by Tracy Newman as having a completely different personality from the characters he played, which were most frequently cops, crime lords, or judges.

[8] 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.