The Spider-Man and The Florida Project actor will host the NBC late-night comedy series on January 29.
He will be joined by musical guest Katy Perry, who is making her fourth appearance on the show.
Dafoe will host the third consecutive show of the year, with Will Forte set as host for January 22’s show, alongside musical guests Måneskin.
Dafoe, a four-time Academy Award nominee, has never hosted the show but he has been lampooned on it when Kate McKinnon spoofed his movie The Lighthouse in 2020.
He currently plays the Green Goblin in Spider-Man: No Way Home and co-stars in Nightmare Alley.
Perry, meanwhile, is making her fourth appearance, having hosted in 2011 and performed in 2010, 2013 and 2017. The American Idol judge is currently headlining her first Las Vegas residency.
The series is produced in association with Broadway Video and comes from creator and exec producer Lorne Michaels.