Grieco worked as a model for Armani, Calvin Klein and Chanel. He played Rick Gardner on One Life to Live from 1985 to 1987. In 1988, Grieco began appearing as Detective Dennis Booker on the shows 21 Jump Street and its spinoff Booker. Grieco's feature film debut was as Michael Corben in If Looks Could Kill (1991) and has appeared in numerous films since then. Later in 1991, he played the young Jewish bootlegger and mobster Benjamin "Bugsy" Siegel in the movie Mobsters. He also appeared in the TV series Marker in 1995. He played himself in the 1998 film A Night at the Roxbury.
In 2009, several years after being encouraged by Dennis Hopper, Grieco publicly revealed that he has been painting since 1991. He calls his work "Abstract Emotionalism".
In 2016, he appeared as himself in an episode of It's Always Sunny in Philadelphia.
