He has also worked with some of Hollywood's top directors including Mike Nichols' Silkwood, Stephen Gyllenhaal's Losing Isaiah, Sydney Pollack's The Firm, Tim Robbins' Bob Roberts, Penny Marshall's A League of Their Own, Taylor Hackford's Dolores Claiborne, Curtis Hanson's LA Confidential and Philip Kaufman's Twisted to name just a few.

He has starred opposite Meryl Streep in The River Wild, Richard Dreyfuss in Lost In Yonkers, Jessica Lange in Losing Isaiah, Ray Liotta and Jamie Lee Curtis in Dominick and Eugene, Sean Penn and Christopher Walken in At Close Range, Debra Winger in A Dangerous Woman, Ashley Judd and Oliver Platt in Simon Birch, Sigourney Weaver and Julianne Moore in A Map of the World. He's also appeared in Blue Car, which was purchased by Miramax from the 2002 Sundance festival, and Harrison's Flowers, opposite Andie Macdowell.

His extensive stage work includes The Three Sisters with Billy Crudup and Marcia Gay Harden, Dance of Death with Sir Ian McKellen and Helen Mirren and Salome with Al Pacino. Television credits include the HBO features In the Gloaming and The James Brady Story and The American Clock for TNT. Strathairn also had a recurring arc on The Sopranos.