While still in college, but having already appeared in films and television, he formed the theater company Malaparte with numerous friends, including Ethan Hawke and Robert Sean Leonard.
Waterston has a number of stage credits, such as the lead role in the 2011 world premiere of Chinglish, by David Henry Hwang, at Chicago's Goodman Theatre.
He also appeared on Law & Order: Special Victims Unit, in the 2008 episode "Inconceivable", as a husband whose wife couldn't conceive without in-vitro fertilization.
He returned to Law & Order: Special Victims Unit, in the 2017 episode “Real Fake News”, playing Congressman Luke Bolton, who gets falsely accused of soliciting underage girls.
Waterston has numerous other appearances on episodes of television dramas, such as Diagnosis: Murder, The Good Wife, The Blacklist and others.