The Hollywood Reporter singled Seimetz out as one of the breakouts of Sundance that year: "As a late-night truck-stop waitress and orphaned lost soul, Seimetz invests Off Hours' dead-end world of tiny tragedies with a hidden, hard-won strength." She appeared in Revenge for Jolly!. In 2012, she made her feature directorial debut with the Florida-based thriller Sun Don't Shine, which she also wrote, produced, and co-edited. The film premiered at South By Southwest to rave reviews. Indiewire wrote: "Her terrific directorial debut was a brilliant noir exercise with less mumbling than raw brawls. She pinned me to my Alamo Drafthouse seat and the film kept me there for the next 82 minutes."

Seimetz is the star of Upstream Color and Pit Stop, both of which premiered at the 2013 Sundance Film Festival. In February, she was added as a series regular to AMC's series The Killing. In season 3, she plays Danette Leeds, a "hard-living, financially strapped single mother whose 14-year-old daughter goes missing".

In June 2014, Starz announced that they had ordered a 13-episode anthology series of the film The Girlfriend Experience, co-written, co-directed, and executive produced by Seimetz and Lodge Kerrigan. This came after the film's creator Steven Soderbergh stated: "I think if I were going to run a studio I'd just be gathering the best filmmakers I could find and sort of let them do their thing within certain economic parameters. So I would call Shane Carruth, or Barry Jenkins or Amy Seimetz and I'd bring them in and go, OK, what do you want to do?" The series was later renewed for a second season, Seimetz will continue to produce, write, and direct episodes.

As of 2016, Amy Seimetz is engaged to filmmaker Shane Carruth.

In 2017, Seimetz appeared in Alien: Covenant, directed by Ridley Scott, and will have roles in Lean on Pete, directed by Andrew Haigh, and My Days of Mercy, opposite Ellen Page.