Wever began her career starring in low budget, independent short and feature films. She has performed in theatre productions, including a performance in Brooke Berman's play Smashing, and in Cavedweller with Deidre O'Connell, both off-Broadway. Since she began her career, Wever has performed in numerous feature films, including: Into the Wild, Neal Cassady, Michael Clayton, ', Signs, The Adventures of Sebastian Cole, Bringing Rain, Tiny Furniture and All I Wanna Do, among others. She has guest-starred on a number of TV shows, including New Girl, The Good Wife, Conviction, ' and The Wire. She also starred in Ed Zwick's ill-fated pilot Quarterlife, with Rachel Blanchard, Austin Nichols, and Shiri Appleby. She also had a recurring role on Studio 60 on the Sunset Strip as Suzanne. Wever is perhaps best known for her role as Zoey Barkow in the series Nurse Jackie, which premiered on Showtime in June 2009. Zoey is described as on the official Nurse Jackie website as "an irrepressibly bubbly trauma nurse, who serves as a comic foil to Edie Falco's hard-bitten titular character". Wever received widespread critical acclaim for her role on the show. Wever was nominated for a Primetime Emmy Award for Outstanding Supporting Actress in a Comedy Series in 2012 and 2013 for her role in Nurse Jackie, winning the award in 2013 and delivering a memorable speech that consisted only of her stunned reaction: "Thanks so much. Thank you so much. I gotta go. Bye." In 2016, Wever had a recurring role on AMC's The Walking Dead as Denise Cloyd. Her character's death toward the end of the sixth season of the series was controversial and sparked outrage on social media with many fans, most notably members of the LGBT community. Wever played a lead role in 2017's miniseries Godless as Mary Agnes McNue, a tough leader of a female-dominated town. She said in interviews that she had been intimidated by the role: "I spent so much of this shoot thinking I would come off as a fool, that nobody would buy me as this and it wouldn't be believable." Many critics nonetheless noted her character as a highlight of the show. Entertainment Weekly titled its review of Godless "Merritt Wever rides tall in Netflix's Godless" and wrote that "no one is more electric than the always extraordinary Merritt Wever". In 2018, she won an Emmy for the role. In 2019, Wever starred in another Netflix miniseries Unbelievable, opposite Toni Collette and Kaitlyn Dever released on September 13, 2019. The series received critical acclaim, with Wever receiving her first Golden Globe Awards nomination for Best Actress- Miniseries or Television Film. In 2020, Wever began starring in the HBOblack comedy thriller series Run opposite Domhnall Gleeson. It was cancelled after one season.