In 1982, while still working as a detective, he made his stage debut in the Steppenwolf Theater Company production of A Prayer for My Daughter, directed by John Malkovich.

Farina played mob boss Jimmy Serrano in the comedy-crime film Midnight Run; and Ray "Bones" Barboni, a rival criminal to Chili Palmer, in Get Shorty.

He played FBI Agent Jack Crawford in Michael Mann's Manhunter, the first film to feature the character Hannibal Lecter.

His other film appearances include Steven Spielberg's Saving Private Ryan, Striking Distance, Another Stakeout, Snatch, The Mod Squad, Reindeer Games, Men of Respect, Big Trouble and Out of Sight.

In a departure from his usual parts, he had a leading-man role, co-starring with Bette Midler, in the romantic comedy That Old Feeling (1997), directed by Carl Reiner.

In 2013, he voiced the father of Daffy Duck's girlfriend on The Looney Tunes Show, and played himself in a 2014 episode of the animated series Family Guy called "The Most Interesting Man in the World," aired posthumously, one of his final acting roles.

In 2004, producers of the television series Law & Order hired him as Detective Joe Fontana, following the death of longtime cast member Jerry Orbach.

In 2006, he left Law & Order for other projects, including the 2007 feature You Kill Me opposite Ben Kingsley and the 2008 What Happens in Vegas with Cameron Diaz and Ashton Kutcher.

He appeared in two television network miniseries based on Joe McGinniss's true-crime books, Blind Faith (1990) and Cruel Doubt (1992).

He made a rare western, portraying legendary lawman Charlie Siringo in a 1995 television movie, Bonanza: Under Attack, a followup to the hit 1960s series.

Again on television, Farina co-starred in the 2012 HBO horse-race gambling series Luck, with Dustin Hoffman, directed by Michael Mann.