He is married to actress Nancy DeCarl; they have one son, Lorenzo Manetti (b. 1980).

Manetti studied acting in Chicago with the Ted List Players. Manetti's first television role was as a young detective in Jack Webb's Chase (1973—74). He next played hot-shot 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 titular role. Manetti's signature role on Magnum, P.I. lasted for the entire eight year run of the series (1980—88). He has also done co-starring roles in 25 feature films and guest starred on many other television shows, including Emergency!, Tenspeed and Brownshoe, Tales from the Darkside, Baa Baa Black Sheep, Battlestar Galactica, Renegade, Quantum Leap, JAG and Walker, Texas Ranger.

Manetti is the author of the semi-autobiographical Aloha Magnum built around his time on Magnum P.I. and anecdotes about fellow cast members and celebrities such as Frank Sinatra, Elvis Presley, and Michelle Pfeiffer. He used to host a "Celebrity Brunch" and own a restaurant at the Plaza Hotel & Casino, when it was owned by his friend D.W. Barrick of Barrick Gaming Corporation.