Wever is perhaps best known for her role as Zoey Barkow in the dark comedy series Nurse Jackie, which premiered on Showtime in June 2009. Zoey is described as "an irrepressibly bubbly trauma nurse, who serves as a comic foil to Edie Falco's hard-bitten (and prescription drug-addicted) titular character" on the official Nurse Jackie website. 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 for her role in Nurse Jackie in 2012 and 2013, 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 towards 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 Netflix 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".