Flanagan wrote, directed, produced, and edited the horror films Absentia (2011), Oculus (2013), Hush, Before I Wake, Ouija: Origin of Evil (all 2016), Gerald's Game (2017), and Doctor Sleep (2019).

Other frequent collaborators include Carla Gugino, Henry Thomas, Samantha Sloyan, Rahul Kohli, Bruce Greenwood, Zach Gilford, Michael Trucco, Annalise Basso, Lulu Wilson, Annabeth Gish, Katie Parker and Alex Essoe.

[2] After graduating, he directed Ghosts of Hamilton Street (2003), filmed in Maryland with local actors,[5] including Scott Graham, whom Flanagan met at Towson.

[2] Made for $70,000 and filmed in his Glendale, California, apartment, Absentia was released direct-to-video but gained popularity when Netflix offered it on its streaming service.

After a year in bankruptcy court, Relativity announced that Before I Wake would be released on April 8, 2016, but missed that date as the company struggled to get back on its feet.

[14] Written by Flanagan and lead actress Kate Siegel, and also starring John Gallagher Jr., Michael Trucco, and Samantha Sloyan, the film had its world premiere at SXSW in March 2016 and was released exclusively on Netflix on April 8, 2016 to positive reviews.

In 2017 Flanagan directed, wrote, and edited the psychological horror film Gerald's Game, based on the 1992 novel of the same title by Stephen King.

[16] In 2018, Flanagan created, wrote, directed, produced, and edited the Netflix supernatural horror series The Haunting of Hill House, based on Shirley Jackson's novel of the same name.

[21] Around the same time, it was also announced that Flanagan had joined frequent collaborator Trevor Macy as a partner in Intrepid Pictures and that the duo had signed an exclusive overall deal with Netflix to produce television content.

[23] Flanagan wrote, directed and served as showrunner on the seven-episode series, which was released in September 2021 to critical acclaim after a production delay in 2020 caused by the COVID-19 pandemic.

[25] In October 2021 it was announced that Flanagan would create The Fall of the House of Usher, an eight-episode limited series for Netflix based on the short story of the same name and other works by Edgar Allan Poe.

[27] In May 2023, it was announced that Flanagan would adapt King's drama novella The Life of Chuck from the short story collection If It Bleeds into a feature film starring Tom Hiddleston and Mark Hamill.

[39] Flanagan's work has attracted praise from figures such as William Friedkin, Stephen King, and Quentin Tarantino for his directing style and lack of reliance on jump scares.

[48][47][49] Flanagan spent years studying various religions, later describing Midnight Mass as a passion project that was "deeply personal" and dealt intimately with his Catholic upbringing and his eventual atheism, as well as his sobriety.