[3] Photographer Alex Harsley put Serrano's work in his first New York City show at his Fourth Street Photo Gallery.

He has shot an array of subject matter including portraits of Klansmen, morgue photos, and pictures of burn victims.

He went into the New York City Subway with lights and photographic background paper to portray the bedraggled homeless, as well as producing some rather tender but sometimes decidedly kinky portraits of couples.

Among these is Piss Christ (1987), a photograph of a plastic crucifix submerged in a glass of the artist's own urine, which caused great controversy when first exhibited.

Serrano, alongside other artists such as Robert Mapplethorpe, Barbara Degenevieve, and Merry Alpern, became a figure whom Senator Jesse Helms, and Senator Alphonse D'Amato, as well as other cultural conservatives, attacked for producing offensive art while others, including The New York Times,[12] defended him in the name of artistic freedom.

[13] Serrano's series Objects of Desire, from the early 1990s, features close-ups of firearms, photographed at the Slidell, Louisiana home of artist Blake Nelson Boyd.

Included is a shot, against a glowing orange background, down the barrel of a loaded .45 revolver (belonging to Boyd's grandfather) that was used by Jonas Mekas for the cover of the April–May–June 2007 Anthology Film Archives catalog.

"[14] Reviewing later work in 2001, Guardian art critic Adrian Searle was not impressed: he found that Serrano's photos were "far more about being lurid than anything else...

[16] Serrano adopted the alter ego "Brutus Faust" to create the full-length album Vengeance Is Mine in July 2010.

"[19] Over the course of several months, Serrano engaged with over 85 homeless individuals in Manhattan and photographed them for a series called Residents of New York, a site-specific public art exhibition on display from May 19 to June 15, 2014, at the West Fourth Street – Washington Square subway station, on LaGuardia Place (between West 3rd and Bleecker Streets), at Judson Memorial Church, and in phone booths and posters around the city.

[21] Serrano initially photographed homeless individuals in the city in 1990 for a series of studio-style portraits titled Nomads.