In 1976 Lithgow acted alongside Meryl Streep in the plays 27 Wagons Full of Cotton, A Memory of Two Mondays and Secret Service at The Public Theatre.

He starred as Dick Solomon in the television sitcom 3rd Rock from the Sun (1996–2001), winning three Primetime Emmy Awards for Best Actor in a Comedy Series.

He also acted in films such as Footloose (1984), Harry and the Hendersons (1987), A Civil Action (1998), Shrek (2001), Kinsey (2004), Rise of the Planet of the Apes (2011), Love Is Strange (2014), Interstellar (2014), Beatriz at Dinner (2017), Late Night (2019), Bombshell (2019), Killers of the Flower Moon (2023), and Conclave (2024).

[6] On the show Finding Your Roots, Lithgow discovered that he is a descendant of eight Mayflower passengers, including colonial governor William Bradford.

In 1973, Lithgow debuted on Broadway in David Storey's The Changing Room at the Morosco Theatre, earning him his first Tony nomination for Featured Actor in a Play and his first win.

[16] In 1976 he starred on Broadway in Arthur Miller's A Memory of Two Mondays opposite Meryl Streep and Tom Hulce at the Playhouse Theatre.

The character was loosely based on the real-life Broadway director and choreographer Michael Bennett, known for his work on Follies, Company, Dreamgirls and A Chorus Line.

Lithgow voiced the character of Yoda in the National Public Radio adaptations of The Empire Strikes Back and Return of the Jedi.

[18] In 1982 and 1983, Lithgow was nominated for the Academy Award for Best Supporting Actor for his performances as Roberta Muldoon in The World According to Garp and as Sam Burns in Terms of Endearment.

In 1991, he starred in the movie Ricochet opposite Denzel Washington as Earl Talbot Blake, a criminal seeking revenge against the policeman who sent him to prison.

In 1994, Lithgow played Franklin Delano Roosevelt in the NBC miniseries World War II: When Lions Roared (also known as Then There Were Giants) directed by Joseph Sargent starring alongside Michael Caine and Bob Hoskins.

In 2001, Lithgow gained recognition for voicing the evil but dwarfish Lord Farquaad in the Academy Award-winning DreamWorks Animation film Shrek alongside Mike Myers, Eddie Murphy and Cameron Diaz.

That same year Lithgow returned to Broadway portraying J.J. Hunsecker in the adaptation of the 1957 film Sweet Smell of Success acting alongside Brian d'Arcy James.

[24] In 2005, Lithgow became the first ever actor to deliver a commencement speech at Harvard University[25] and received an honorary Doctor of Arts from his alma mater.

[32] In 2007, Lithgow played Malvolio in the Royal Shakespeare Company's production of Twelfth Night, at The Courtyard Theatre, Stratford-upon-Avon, in the United Kingdom.

On March 5, 2009, Lithgow made a cameo on NBC's 30 Rock acting in the episode "Goodbye, My Friend" with several references to his role in Harry and the Hendersons.

Lithgow starred alongside Dianne Wiest, Patrick Wilson and Katie Holmes in her Broadway debut at the Schoenfeld Theatre.

[39] In 2010, Lithgow starred in the Off-Broadway production of Douglas Carter Beane's comedy Mr & Mrs Fitch alongside Jennifer Ehle at the Second Stage Theater which ran from February 22, 2010, to April 4, 2010.

In September 2011, Lithgow was featured in a one-night only production of Dustin Lance Black's play 8, a staged reenactment of the federal trial that overturned California's Prop 8 ban on same-sex marriage—as Attorney Theodore Olson to raise money for the American Foundation for Equal Rights.

The film received a 94% on Rotten Tomatoes with the consensus reading "Held aloft by remarkable performances from John Lithgow and Alfred Molina, Love Is Strange serves as a graceful tribute to the beauty of commitment in the face of adversity.

[46] Lithgow during the 2010s appeared in Rise of the Planet of the Apes (2011),[47] Jay Roach's The Campaign (2012), Judd Apatow's This Is 40 (2012), Christopher Nolan's Interstellar (2014), and Tommy Lee Jones' The Homesman (2014).

[52] During this time he also acted in Gavin O'Connor's The Accountant, John Madden's Miss Sloane (2016), Sean Anders's Daddy's Home 2 (2017), Trish Sie's Pitch Perfect 3 (2017), and a new adaptation of Stephen King's novel, Pet Sematary (2019).

That same year he portrayed Fox News CEO Roger Ailes in the film Bombshell which starred Charlize Theron, Margot Robbie, and Nicole Kidman.

On June 28, 2021, Showtime confirmed that Lithgow would reprise his role of Arthur Mitchell in the 10-episode Dexter limited series, with Clyde Phillips returning as the head writer.

[62] The film co-starred Leonardo DiCaprio, Lily Gladstone, and Robert De Niro and received ten Academy Award nominations including for Best Picture.

[65][66] Also in 2024, he participated in the animated movie Spellbound with Rachel Zegler, Nicole Kidman, Javier Bardem and Nathan Lane, released on Netflix.

Farkle and Friends features the vocal talents of Lithgow and Bebe Neuwirth, backed by the Bill Elliott Swing Orchestra as well.

Produced by J. C. Hopkins, the album features guest appearances by Madeleine Peyroux, Wayne Knight, Sherie Rene Scott and Maude Maggart.

Staged on the altar of New York City's Riverside Church, the reading was created by playwright Robert Schenkkan and narrated by Annette Bening.

It also featured Kevin Kline as Mueller, Joel Grey as Jeff Sessions, Jason Alexander as Chris Christie and Alfre Woodard as Hope Hicks.