In 2018, Nixon ran for Governor of New York as part of the Working Families Party challenging Democratic incumbent Andrew Cuomo.

[21] Nixon's first onscreen appearance (at 8 years old) was as an imposter on To Tell the Truth, where her mother worked, pretending to be a junior horse riding champion.

[24] Alternating between film, TV, and stage, she did projects like the 1982 ABC movie My Body, My Child, the features Prince of the City (1981) and I Am the Cheese (1983), and the 1982 Off-Broadway productions of John Guare's Lydie Breeze.

In 1984, while a freshman at Barnard College, Nixon made theatrical history by simultaneously appearing in two hit Broadway plays directed by Mike Nichols.

[27] She landed her first major supporting role in a movie as an intelligent teenager who aids her boyfriend (Christopher Collet) in building a nuclear bomb in Marshall Brickman's The Manhattan Project (1986).

Nixon succeeded Marcia Gay Harden as Harper Pitt in Tony Kushner's Angels in America (1994),[31] received a Tony nomination for her performance in Indiscretions (Les Parents Terribles) (1996), her sixth Broadway show,[32] and, although she originally lost the part to another actress, eventually took over the role of Lala Levy in the Tony-winning The Last Night of Ballyhoo (1997).

Nixon was a founding member of the Off-Broadway theatrical troupe Drama Dept.,[33] which included Sarah Jessica Parker, Dylan Baker, John Cameron Mitchell and Billy Crudup among its actors, appearing in the group's productions of Kingdom on Earth (1996), June Moon and As Bees in Honey Drown (both 1997), Hope is the Thing with Feathers (1998), and The Country Club (1999).

[35] Nixon next had her first leading role in a feature, playing a video artist who falls in love, despite her best efforts to avoid commitment, with a bisexual actor who just happens to be dating a gay man (her best friend) in Advice from a Caterpillar (2000), as well as starring opposite Scott Bakula in the holiday television movie Papa's Angels (2000).

In 2002, she also acted in the indie comedy Igby Goes Down, and her turn in the theatrical production of Clare Boothe Luce's play The Women was captured for PBS' Stage on Screen series.

Post-Sex and the City, Nixon made a guest appearance on ER in 2005, as a mother who undergoes a tricky procedure to lessen the effects of a debilitating stroke.

In 2006, she appeared in David Lindsay-Abaire's Pulitzer Prize-winning drama Rabbit Hole in a Manhattan Theatre Club production,[36] and won the Tony Award for Best Actress in a Leading Role (Play).

[37] In 2008, she revived her role as Miranda Hobbes in the Sex and the City feature film, directed by HBO executive producer Michael Patrick King and co-starring the cast of the original series.

[38] Also in 2008, she won an Emmy for her guest appearance in an episode of Law & Order: Special Victims Unit, portraying a woman pretending to have dissociative identity disorder.

The award is presented to an openly LGBTQ media professional "who has made a significant difference in promoting equality for the LGBT community".

[43] In 2012, Nixon also starred as Petranilla in the TV miniseries of Ken Follett's World Without End broadcast on the ReelzChannel, alongside Ben Chaplin, Peter Firth, Charlotte Riley, and Miranda Richardson.

[44][45][46][47] Nixon played the leading role of reclusive American poet Emily Dickinson in the biographical film A Quiet Passion directed and written by Terence Davies.

Since 2022 she took a leading role of Ada Brook in another HBO Max show The Gilded Age starring alongside Louisa Jacobson, Christine Baranski, and Carrie Coon.

De Blasio credited Nixon and union leader George Gresham as the two "architects of (his) campaign" in the Democratic primaries, when he defeated the favorite Christine Quinn.

[54] In the 2020 Democratic Party presidential primaries, Nixon endorsed Bernie Sanders before campaigning for him in early February 2020 in Las Vegas.

A candidate who is too beholden to big money and the establishment and just basically doesn't want to rock the boat is never going to be a powerful enough counterbalance to what Donald Trump has to offer.

"[55] In 2023, Nixon signed an open letter expressing "serious concerns about editorial bias" in reporting by the New York Times on transgender people.

[59] Her platform focused on income inequality, renewable energy, establishing universal health care, stopping mass incarceration in the United States, and protecting undocumented children from deportation.

Nixon was expected to secure the nomination of the Working Families Party of New York during its annual convention in April 2018, thus guaranteeing her a spot on the general election ballot.

[62] On April 15, Nixon won 91.5 percent of the vote at the Party's statewide committee meeting after Cuomo withdrew himself from consideration at the last minute.

[69][70][71][72] On June 22, 2018, during a campaign event in New York City, Nixon referred to the U.S. Immigration and Customs Enforcement (ICE) as a “terrorist organization” and called for the agency to be abolished.

She contributed to a video series, published by the Palestine Festival of Literature, in support of South Africa's motion, accusing Israel of genocide against civilians in Gaza.

[97] She initially decided not to go public with her illness because she feared it might hurt her career,[98] but in April 2008, she announced her battle with the disease in an interview with Good Morning America.

She convinced the head of NBC to air her breast cancer special in a prime time program,[98] and became an ambassador for Susan G. Komen for the Cure.