He is best known for his roles as Jame Gumb (Buffalo Bill) in the film The Silence of the Lambs (1991) and Leland Stottlemeyer in the television series Monk (2002–2009).

Levine's other notable roles are in the films Nowhere to Run (1993), Heat (1995), Bullet (1996), The Fast and the Furious (2001), The Manchurian Candidate (2004), Memoirs of a Geisha (2005), American Gangster (2007), Shutter Island (2010), Jurassic World: Fallen Kingdom (2018), and The Report (2019).

He was gradually able to branch out into other types of roles, such as a member of Al Pacino's police unit in Heat, and astronaut Alan Shepard in the HBO mini-series From the Earth to the Moon.

He played Detective Sam Nico in the 2003 film Wonderland, based on the gruesome murders in the Hollywood Hills.

From 2002 to 2009, he co-starred as Captain Leland Stottlemeyer on USA Network's detective series Monk, starring Tony Shalhoub.

In 2013, he had a major supporting role in the FX murder mystery series The Bridge as Lieutenant Hank Wade, commander of a police homicide unit in a Texas border city.