[5] Early plays during his first year at Yale include Say You Love Satan, "a romantic comedy spoof of the Omen movies", and The Muckle Man, "a serious family drama with supernatural overtones"; good reviews on summer productions of those helped him get a professional agent.

[6] Rough Magic, an interpretation of Shakespeare's The Tempest in which Caliban escapes from Prospero's island and finds himself in present-day New York City, was produced at Yale during his last year there.

[6] Although he wrote some plays in high school, it was after college, while working as a publicist at the Shakespeare Theatre, that Aguirre-Sacasa had an opportunity to attend a week-long playwriting workshop under Paula Vogel at Arena Stage in Washington, D.C.[6] He recalled in 2003 that Vogel held one of her periodic playwriting "boot camps" in the area: ...Paula's a great playwright and a really extraordinary teacher.

[6]On April 4, 2003, Dad's Garage Theatre Company in Atlanta was scheduled to debut Aguirre-Sacasa's new play, Archie's Weird Fantasy, which depicted Riverdale's most famous resident coming out of the closet and moving to New York.

Dad's Garage artistic director Sean Daniels said, "The play was to depict Archie and his pals from Riverdale growing up, coming out and facing censorship.

In 2006, his semi-autobiographical Based on a Totally True Story (about a comic-book writer/playwright struggling with new-found success and boyfriend problems) was staged at the prestigious Manhattan Theatre Club in New York.

[9] Good Boys and True, about a graphic sex tape that begins circulating around an all-boys prep school outside Washington, D.C., premiered at Chicago's Steppenwolf Theatre in winter 2008.

[10] In mid-2009, the Round House Theatre in Bethesda, Maryland, premiered his play The Picture of Dorian Gray, based on the novel by Oscar Wilde.

[citation needed] In 2011, Aguirre-Sacasa was approached by the producers of the troubled Broadway musical Spider-Man: Turn Off the Dark to help rewrite its script.

[18] In April 2013, Aguirre-Sacasa wrote the book for a musical based on Bret Easton Ellis's novel American Psycho, which ran in London from December 3, 2013, to January 25, 2014.

In addition, he is the series developer of Riverdale, Katy Keene, Chilling Adventures of Sabrina and Pretty Little Liars: Original Sin.