Baena began his career as a screenwriter, co-writing the 2004 comedy film I Heart Huckabees and, around the same time, seeing his script for Life After Beth enter production before being shelved.

Baena, as an independent filmmaker, then expanded to directing and filmed Life After Beth as his directorial debut, starring Aubrey Plaza and released in 2014.

Working with producer Liz Destro, and reuniting with Plaza as well as an expanding group of frequent collaborators, Baena was then writer-director for Joshy (2016) and The Little Hours (2017), which both became critically acclaimed and found a cult audience.

Among the performers in these films was Alison Brie, with whom Baena struck up a writing partnership and created works produced by Duplass Brothers Productions.

[7] His first stepmother was manic depressive, and under Florida's Baker Act was frequently institutionalized but then released, with Baena later commenting on systemic challenges in mental health care.

The two ended up collaborating on four scripts together, including I Heart Huckabees, which Russell directed in 2004, and Jay Roach's Meet the Fockers (also 2004), for which they made uncredited revisions.

[18][19] Baena had planned for the comedy-drama Joshy to be his directorial debut, but actor and collaborator Adam Pally had to postpone for personal reasons.

"[24] Life After Beth received mixed reviews; the Rotten Tomatoes (RT) critics' consensus suggested the idea was too thin to sustain a whole film, though bolstered by Plaza's performance.

[10] When production resumed on Joshy, Baena provided his large comedic cast with a 20-page outline, rather than a script, as an experiment to "keep people in the moment."

[27] The film's RT critics' consensus highlighted Baena's direction for "strik[ing] a unique, disarmingly heartfelt blend of dark humor and tragedy".

[51][52] Both actresses were involved in different capacities in Baena's only television work, Cinema Toast, a 2021 anthology series that he created and executive produced.

[53][54][55] Having formed a friendship after working on previous movies, and knowing of the creative risks Baena liked to take, Brie pitched the idea for a drama about fear of mental illness to him while on a hike.

[64] He "never really audition[ed], ever" for his films, saying he was inspired by Federico Fellini choosing performers based on seeing them in a more natural setting than a line reading.

He also found it advantageous to work with familiar actors due to his own "slightly nontraditional way" of writing and directing, so that he could rely on performers who understood his process.

[32][34] Baena was renowned for the game nights he hosted, creating a social environment among filmmakers and friends that was reflected on his film sets.