Russo's first role in his acting career was in the 1981 made-for-television movie Chicago Story. He then went on to star in many hit films of the 1980s.

His big break (but small role) came in the 1982 classic comedy film Fast Times at Ridgemont High, as a convenience store robber. In 1984, he appeared in Beverly Hills Cop as Mikey Tandino, a friend of Axel Foley who is murdered. That same year he starred in The Cotton Club and played small-time hood Bugsy in Sergio Leone's Once Upon a Time in America. Russo's other big role was as a brutal rapist in the 1986 drama Extremities, opposite Farrah Fawcett. He starred in the 1988 drama-suspense-thriller film Freeway.

Russo's film roles in the 1990s include State of Grace (1990), A Kiss Before Dying (1991) and My Own Private Idaho (1991). Russo also had roles in the 1994 Western Bad Girls, the 1997 hit films The Postman, and Donnie Brasco. In 2009 he had a small role in Michael Mann's Public Enemies as a member of John Dillinger's gang.

In 2003, Russo was reunited with his co-star from The Postman, Kevin Costner, in the Western film Open Range. He made guest appearances in many TV dramas and movies, including The Equalizer, Miami Vice, CSI, CSI: Miami and Las Vegas.

In the summer of 2009, Russo starred in the psychological thriller 7E with Brendan Sexton III, John Savage and Natasha Lyonne. The film was released on December 10, 2013. Russo had a supporting role in Quentin Tarantino's 2012 film Django Unchained.

Russo was born in New York City, New York, to an Italian father and German mother. A graduate of New York University (NYU), he wrote and starred in the prize-winning short film The Candy Store. Before his first break in acting, he drove for a cab company, worked as a construction worker and a gravedigger. He was raised in Flushing, New York and spent his formative years on 156th street .