Dubbed a scream queen for her extensive work in the horror genre, Siegel is known for her collaborations with her husband, Mike Flanagan.

[2] That year she went on to star in Hacia La Oscuridad, which had its world premiere at the Tribeca Film Festival on April 28, 2007.

[12] In 2016, Siegel starred as a deaf-mute woman beset by a killer in the horror-thriller Hush, a film on which she also made her screenwriting debut, co-writing with Flanagan.

[16][17] In 2017, Siegel starred alongside Carla Gugino and Bruce Greenwood in the film adaptation of Stephen King's Gerald's Game, which was also directed by Flanagan.

[19] In 2018, Siegel had a starring role as Theodora Crain in the Netflix supernatural horror series The Haunting of Hill House, based on Shirley Jackson's 1959 novel of the same name.

[22] Siegel portrayed Erin Greene in Netflix's Midnight Mass, which was written and directed by Flanagan, and co-starred her castmate from The Haunting of Hill House Henry Thomas.

In July 2024, she was confirmed to make her directorial debut, as she would direct a segment for V/H/S/Beyond, which was released exclusively on Shudder on October 4, 2024.