The 28-year-old Gossip Girl star stars as Sasha in the upcoming romantic comedy, while Brody plays Tim, the man who comes between her and her best friend.
"That came along just by chance," she said of working with her husband. "I was like, 'I'm gonna be playing the person you're not dating. That OK? I'm gonna be playing the opposite of that.' And yeah, I'm biased -- but he's incredible in it."
Meester and Brody previously worked together in the 2011 film The Oranges. The pair began their very-private relationship after meeting on set and married in February 2014.
Meester currently stars in the Broadway adaptation of John Steinback's Of Mice and Men alongside James Franco. Her film Life Partners will hit theaters on April 18.