As a guest star, Berkeley portrayed Sheriff Thomas McAllister on the CBS drama The Mentalist (2008–2013) and Gregory on the AMC post-apocalyptic horror The Walking Dead (2016–2018).

A casting agent spotted Berkeley in a play written by Reynolds Price called Early Dark and encouraged him to move to Hollywood.

[4] Berkeley began playing roles in 1981, with early appearances in M*A*S*H, Cagney & Lacey, Remington Steele, Miami Vice, Moonlighting, and The A-Team.

[6] He has appeared in North Country,[6] Terminator 2: Judgment Day, Phoenix, Kick-Ass,[6] A Few Good Men, The Rookie, Candyman, Apollo 13, Leaving Las Vegas, Gattaca, The Rock, Air Force One, Sid and Nancy,[6] Amistad, Shanghai Noon,[6] Barb Wire[6] and Timecode.

He also voiced Quentin Beck / Mysterio on The Spectacular Spider-Man, Captain Atom in Superman/Batman: Public Enemies and Dr. Kirk Langstrom in Son of Batman.

[12] In 2013, Berkeley won the Streamy Award "Best Male Performance, Drama"[13] for his starring role in the acclaimed web series The Booth at the End.