Manetti studied acting in Chicago with the Ted List Players. His first television role was as a young detective in Jack Webb's Chase (1973–74). He would go on to play pilot "Bobby Boyle" in Baa Baa Black Sheep (1976–78) with Robert Conrad. He followed this up with a role as a bookie on the short-lived NBC series, The Duke (1979), which also featured Conrad in the title role.
Manetti's signature role on Magnum, P.I. lasted for the entire eight year run of the series (1980–88). He also had co-starring roles in 25 feature films and guest starred on many other television shows, including Emergency!, Tenspeed and Brownshoe, Fantasy Island , Battlestar Galactica, Renegade, Quantum Leap, JAG and Walker, Texas Ranger. Manetti also had a minor role in the 1993 film CIA II: Target Alexa.
Since July 2011, Larry and Nancy Manetti have hosted a weekly radio program on CRN Digital Talk Radio Networks.
Manetti had joined CBS's revived version of Hawaii Five-0 in the recurring role of "Nicky 'The Kid' Demarco". The character is described as "a local lounge legend ... [who], back in the day, was mentored by the one and only Frank Sinatra.