He is best known for his portrayal of White House Deputy Chief of Staff Josh Lyman in the NBC television political drama The West Wing (1999–2006), for which he was nominated for three consecutive Primetime Emmy Awards from 2001 to 2003, winning in 2001.

Since 2018, Whitford has portrayed Commander Joseph Lawrence in Hulu dystopian drama The Handmaid's Tale, for which he won his third Primetime Emmy Award in 2019.

[5] He majored in English and theatre at Wesleyan University (where he was a roommate of producer Paul Schiff), graduating with a Bachelor of Arts in 1981.

explored Whitford's ancestry in an August 2022 episode, including ancestors who fought in a crucial American Civil War battle.

Whitford film roles during the 1980s and 1990s included Elisabeth Shue's boyfriend Mike Todwell in Adventures in Babysitting (1987), Roger Latimer in Revenge of the Nerds II: Nerds in Paradise (1987), Jamie Kemp in Presumed Innocent (1990), Charles Phalen in Young Guns II (1990), Dr. Tyler in Awakenings (1990), Al Pacino's brother-in-law Randy Slade in Scent of a Woman (1992), FBI sharpshooter Bobby Lee in A Perfect World (1993), lawyer Jamey Collins in Philadelphia (1993), Assistant U.S. Attorney Thomas Fink in The Client (1994), antagonist Eric Gordon in Billy Madison (1995), and Lloyd Charney in Bicentennial Man (1999).

Whitford also wrote two episodes of the series ("Faith Based Initiative" in the sixth season and "Internal Displacement" in the seventh).

After The West Wing ended in May 2006, Whitford appeared in Sorkin's later series Studio 60 on the Sunset Strip playing the role of Danny Tripp.

He appeared in the season three finale of The Mentalist as a minion of and decoy for "Red John", the long-sought nemesis of the show's protagonist Patrick Jane.

On September 15, 2011, he starred in the one-night-only staged reading of 8, a play that chronicles the trial surrounding California's Proposition 8, written by Dustin Lance Black.

[17][18] In 2017, Whitford played Dean Armitage, a father and neurosurgeon, in the racially themed horror film Get Out,[19] and antagonist Arthur Parsons in the political thriller The Post.

[36] He serves on the Board of Advisors of Let America Vote, an organization founded by former Missouri Secretary of State Jason Kander that aims to end voter suppression.

[38] In 2011, Whitford spoke at a protest in his native Madison, Wisconsin, in opposition to Governor Scott Walker's budget repair bill.

[45] That same year, Whitford appeared in a public service announcement in support of abortion rights alongside other cast members of The Handmaid's Tale.