[2] Moss began acting in the early 1990s and first gained recognition for playing the youngest daughter of President Josiah Bartlet, in the NBC political drama series The West Wing (1999–2006).

For producing and starring as June Osborne in the Hulu dystopian drama series The Handmaid's Tale (2017–present), Moss won two Primetime Emmy Awards.

[9] She provided the voice of Holly DeCarlo, a main character in the TV special Frosty Returns (1992) and of Michelle in the animated film Once Upon a Forest (1993).

The following year, she appeared in the remake of the Walt Disney Pictures film Escape to Witch Mountain (1995) and played a young Ashley Judd in the biopic Love Can Build a Bridge (1995).

[9] She also had a supporting role in the drama Separate Lives (1995) opposite Jim Belushi and Linda Hamilton, and a minor part in the black comedy The Last Supper (1995).

[9] Her character became integral to the fourth season of the show; in a retrospective on the series The Atlantic noted: "Aaron Sorkin made [Moss] the centerpiece of the explosive fourth-season finale where he basically engineered the most insane cliffhanger possible.

[13] Moss had a supporting role in the 2005–2006 horror series Invasion,[9] and appeared in television again on a 2007 episode of Grey's Anatomy entitled "My Favorite Mistake".

[21] While a series regular on Mad Men, Moss made her Broadway debut in October 2008, playing the role of Karen in the 20th Anniversary revival of Speed-the-Plow by David Mamet.

He added, "Ms. Moss proves the lie in that assessment, bringing a naked clarity to her unvarnished, tinny-voiced Karen that makes the play hang together in ways it didn’t before.

[24] In 2011, Moss made her West End debut as Martha Dobie in Lillian Hellman's play The Children's Hour, opposite Keira Knightley and Rebecca Hall.

[25] Michael Billington of The Guardian described her performance as "Outstanding" noting, "Moss's achievement, in fact, is to combine the everyday busyness of a working teacher with subtle hints she has a suppressed longing that transcends mere friendship.

[33] After production on Mad Men had wrapped, Moss collaborated again with Alex Ross Perry, starring in Queen of Earth (2015), a psychological thriller opposite Katherine Waterston and Patrick Fugit, in which she plays a mentally unstable woman who unravels at a vacation home in the company of her close friends.

Laing,[37] and co-starred in the film adaptation of Anton Chekhov's play The Seagull alongside Saoirse Ronan, Annette Bening, and Corey Stoll.

[41] Liz Shannon Miller of IndieWire wrote, "[The show] owes a tremendous amount to Moss as its star...as an actor, she has to communicate silently without revealing too much about what the character really thinks.".

"[42] In 2018, Moss had a lead role in a short film for the song "On the Nature of Daylight", by British composer Max Richter, from his album The Blue Notebooks.

[43] Moss reunited with Alex Ross Perry for Her Smell (2018), portraying the role of a fictional rock star whose band breaks up over her self-destructive behavior,[44] and appeared in The Old Man & the Gun, directed by David Lowery.

[48][49] Later that year, she starred in The Kitchen, alongside Melissa McCarthy and Tiffany Haddish, which follows three housewives who, after their mobster husbands are sent to prison, continue to operate their business.

[51][52] She also had the starring role in the horror-thriller film The Invisible Man, alongside Oliver Jackson-Cohen and Storm Reid, which was released on February 28, 2020, to critical acclaim.

[58] In his review, Daniel Fienberg of The Hollywood Reporter declared, "No single actor in the past 25 years has a more reliable television track record than Elisabeth Moss".

"[60] Ben Travers of IndieWire wrote a mixed review praising Moss as an actress and comparing her to "Julia Louis-Dreyfus and Carrie Coon" but described the spy thriller series as "regressive to the genre itself".