Sirico was born in Midwood, Brooklyn to Sicilian parents. Sirico has played gangsters in a number of films, including Mob Queen, Gangsters, Love and Money, Fingers, Defiance - 1980, The Last Fight, Goodfellas, Innocent Blood, Bullets Over Broadway, The Pick-up Artist, Mighty Aphrodite, Gotti, Cop Land, and Mickey Blue Eyes. He also played policemen in the films Dead Presidents and Deconstructing Harry.

Before turning to acting, Sirico was reportedly a mob associate of the Colombo crime family serving under Carmine "Junior" Persico and had been arrested twenty-eight times. There is a Sopranos reference to this fact when Paulie says "I lived through the seventies by the skin of my nuts when the Colombos were goin' at it." In 1967, he was sent to prison for robbing a Brooklyn after hours club, but was released after serving thirteen months. In 1971, he pled guilty to felony weapons possession and was sentenced to an "indeterminate" prison term of up to four years, of which Sirico ended up serving twenty months. In an interview in Cigar Aficionado magazine, Sirico said that during his imprisonment, he was visited by an acting troupe composed of ex-cons, which inspired him to give acting a try. According to a court transcript, at the time of his sentencing, he also had pending charges for drug possession. Sirico appeared in a 1989 documentary about life, The Big Bang by James Toback, in which he discussed his earlier life.

He currently lives in Brooklyn, New York. His mother, who lived with Sirico, died in 2003. Sirico's brother, Robert Sirico, is a Catholic priest and co-founder of the free-market Acton Institute.

Sirico has stated that politically he is a "far-to-the-right Republican." He donated $1,200 to Rudolph Giuliani's presidential campaign.

Other acting work by Sirico: