While "Firefly" launched Morena Baccarin's career, 2016's "Deadpool" put her on the map in the eyes of every Marvel fan. In an interview with People TV's Couch Surfing, she described shooting the movie as "one of the best times of [her] life ... it was creative and fulfilling." "Deadpool" stars Ryan Reynolds as Deadpool himself and Baccarin plays his love interest, Vanessa. Baccarin was drawn to the script thanks to its "off-kilter" and "offensive" humor, which she told Rotten Tomatoes balances out the heartfelt moments of her romance. She also found it refreshing that while her character is the love interest in the film, she's tough and can hold her own.

In 2018, Baccarin reprised her role as Vanessa in "Deadpool 2." While promoting the film, the actor admitted to People that kissing actor Ryan Reynolds was akin to "kissing a giant latex condom." With the prosthetics Ryan Reynolds wears in the film, it was challenging for Beccarin to have chemistry with the actor. In the interview, she described the difficulty of connecting and reacting to someone when you cannot see their face. That wasn't the only challenging aspect of filming, though.

As Baccarin told "Good Morning America," a dream sequence that didn't make it into the movie required Baccarin and Reynolds to be underwater. For the scene, Baccarin was strapped into a chair and weighted down while underwater to prevent her from floating away, which was terrifying to Baccarin as she said she has a "huge phobia of being underwater." Despite the scene not making the final cut, "Deadpool 2" saw huge success, earning $784 million worldwide (via The Hollywood Reporter).