Ficarra met John Requa at Pratt Institute, where both were studying film. After college they went to work in animation for the TV channel Nickelodeon.
As writers they wrote the comedy films Cats & Dogs (directed by Lawrence Guterman), Bad Santa (directed by Terry Zwigoff), and Bad News Bears (directed by Richard Linklater).
In 2009 they made their directorial debut with their self-penned I Love You Phillip Morris, based on the life of con man Steven Russell.
Their subsequent release was the comedy Crazy, Stupid, Love starring Steve Carell, Ryan Gosling, Emma Stone and Julianne Moore, again directed with Requa, released in July 2011.
With Requa and Charlie Gogolak he has formed the production company Zaftig Films.
The pair also directed Focus, starring Will Smith and Margot Robbie, and Whiskey Tango Foxtrot, starring Tina Fey and Robbie.
As of August 2017, Ficarra and Requa are in final negotiations to co-direct and co-write a film featuring Harley Quinn and The Joker set in the DC Extended Universe with Margot Robbie and Jared Leto reprising their roles.