[4] On the big screen, Waterston played Nick Carraway in The Great Gatsby (1974) earning a Golden Globe Award for Best Supporting Actor – Motion Picture nomination.

Other notable roles include in Rancho Deluxe (1975), Hopscotch (1980), Heaven's Gate (1980), The Man in the Moon (1991), Serial Mom (1994), Nixon (1995), Miss Sloane (2016) and On the Basis of Sex (2018).

The play was directed by Gene Frankel, and he acted alongside Stacy Keach as Buffalo Bill, Manu Tupou as Sitting Bull, and other actors such as Tom Aldredge, Kevin Conway, Charles Durning, and Raul Julia.

[16][17] He went on to appear as bond salesman Nick Carraway in the 1974 feature film version of The Great Gatsby acting alongside Robert Redford, Mia Farrow, and Bruce Dern.

[5] The following year, Waterston acted in the neo-Western comedy film Rancho Deluxe (1975) starring Jeff Bridges, Elizabeth Ashley, and Harry Dean Stanton.

[18] Waterston made his first collaboration with Woody Allen playing Mike in the drama Interiors (1978) starring Diane Keaton, Geraldine Page, Maureen Stapleton, and E.G. Marshall.

In 1980, he starred in Benefactors alongside Glenn Close, Mary Beth Hurt, and Simon Jones at The Brooks Atkinson Theatre on Broadway.

[5] In 1984, Waterston played American journalist Sydney Schanberg in the British drama The Killing Fields, opposite Haing S. Ngor and John Malkovich.

[21][22] Waterston reunited with Woody Allen playing David, a romantic interest for Dianne Wiest and Mia Farrow in Hannah and Her Sisters (1986), Peter in September (1987), and Ben, a rabbi who is losing his eyesight Crimes and Misdemeanors (1989).

[25] In 1994, Waterston debuted as Executive Assistant District Attorney Jack McCoy in the fifth season of the NBC television series Law & Order created by Dick Wolf.

He made a popular cameo appearance on a 1995 episode of Saturday Night Live as himself, extolling the virtues of Old Glory Insurance, meant to protect the elderly from robot attacks.

[32] On February 12, 2009, Waterston portrayed Abraham Lincoln in Earl Robinson's "The Lonesome Train: A Music Legend for Actors, Folk Singers, Choirs, and Orchestra" at the Riverside Church in New York City.

[33][34] Waterston has had several other high profile television roles, including his portrayal of cable news president Charlie Skinner in The Newsroom, an HBO series by Aaron Sorkin.

[35] Waterston acted opposite Jeff Daniels, Emily Mortimer, Dev Patel, Olivia Munn, and Jane Fonda.

[36][37] In 2015, Waterston joined the cast of the Netflix series Grace and Frankie, starring alongside Martin Sheen, Jane Fonda and Lily Tomlin.

[citation needed] In 2017, he played Marshal John Cook in the Netflix western limited series Godless opposite Jeff Daniels and Michelle Dockery.

On February 2, 2024, it was revealed that Waterson would be leaving Law & Order after 20 seasons, with his renowned character Jack McCoy, who he also played for 405 episodes being replaced by a new D.A.

[44] Waterston received the Goodermote Humanitarian Award from the Johns Hopkins Bloomberg School of Public Health in 2012 for his longtime support of refugees around the world.

[51] On October 18, 2019, Waterston was arrested outside the U.S. Capitol in Washington, D.C., with Grace and Frankie co-star Jane Fonda, for protesting the Trump administration's policies concerning climate change.

[52] Waterston received an Academy Award nomination for Best Actor for his performance in The Killing Fields (1984), losing to F. Murray Abraham for his role in Amadeus (1984).

[53] AllMovie historian Hal Erickson characterized Waterston as having "cultivated a loyal following with his quietly charismatic, unfailingly solid performances.