His play The Motherfucker With the Hat was nominated for seven Tony Awards and premiered on Broadway in 2011 and featured Bobby Cannavale, Chris Rock, Elizabeth Rodriguez, Annabella Sciorra and Yul Vazquez.
[13] His award-winning recent play Halfway Bitches Go Straight To Heaven, directed by John Ortiz in 2019 in a LAByrinth Theater/Atlantic Theater co-production, features a cast of 18 plus a goat, and garnered Obie Awards for its two stars, Liza Colón-Zayas and Elizabeth Rodriguez.
[16] His play Our Lady of 121st Street ran originally in an Off-Broadway production by the LAByrinth Theater at Center Stage/NY and then transferred to the Union Square Theatre from March 6, 2003, to July 27, 2003.
Guirgis collaborated with Academy Award nominated director Baz Luhrmann on The Get Down, a Netflix Series about the birth of hip-hop in the 1970s.
[29] He developed and directed Liza Colón-Zayas' play Sistah Supreme for Danny Hoch's Hip Hop Theater Festival in 2000[30] Marco Greco's award-winning Behind the Counter with Mussolini at the York Theatre (1998 in New York)[31] and Los Angeles (1999 and 2002),[32] and directed Melanie Maras' Kiss Me on the Mouth for InViolet Rep in 2009.
[34] He has had supporting roles in films such as Todd Solondz's Palindromes (2004),[35] Brett C. Leonard's Jailbait (2004), and Kenneth Lonergan's Margaret (2011).
[36] Other credits include the 1997 Law & Order episode "Terminal" and films such as Meet Joe Black (1998),[37] Blackbird (2007),[38] Trainwreck: My Life as an Idiot (2007),[39] Noise (2007),[40] Synecdoche, New York (2008),[41] and Philip Seymour Hoffman's directorial debut Jack Goes Boating (2010).
In 2017 Guirgis was embroiled in a publicized debate with a small theater in San Francisco which had produced an edited version of The Last Days of Judas Iscariot.
[42][43] Guirgis has used improvisational theater to "teach HIV/AIDS prevention, conflict resolution, and leadership" in prisons, schools, shelters, and hospitals.
[44] Guirgis was close professional and personal friends with late actor Philip Seymour Hoffman[42] with whom he was a frequent collaborator.
Guirgis is the recipient of new play commissions from Manhattan Theatre Club, Center Theater Group, and South Coast Repertory.