Strathairn appeared in supporting roles in many notable films such as A League of Their Own (1992), Sneakers (1992), The Firm (1993), The River Wild (1995), Lincoln (2012), Nomadland (2020), and Nightmare Alley (2021). He is a frequent collaborator with director John Sayles, who is a fellow graduate of Williams College.
On television, Strathairn is known for his recurring roles in The Sopranos (2004), Alphas (2011–2012), The Blacklist (2015–2016), Billions (2017–2019), and The Expanse (2018–2019). He received a Primetime Emmy Award win and a Golden Globe Award nomination for his performance in the HBO television film Temple Grandin (2010).