He is most famous for his graphic novels, especially My Friend Dahmer, the international bestseller which won an Angoulême Prize, and earlier for his comic strip The City, which appeared in a number of alternative newspapers from 1990 to 2014.

Punk Rock & Trailer Parks is a fictional story that follows one remarkable young man named Otto who, through talent, wits and sheer chutzpah becomes a star in the Rubber City punk scene and has memorable meetings with underground luminaries of the day, including Wendy O. Williams, Stiv Bators, Lester Bangs, and The Clash.

The original self-published comic book was nominated for an Eisner Award and was adapted and staged as a one-act play by the NYU Theater Dept.

[14] Trashed (Abrams Comic Arts, 2015), an Eisner Award-winning[15] fictional story based on Derf's experiences as a 21-year-old garbageman, was published as a 240-page graphic novel.

The 288-page book, which is heavily researched and includes copious footnotes at the end, is a dramatic recreation of those four bloody days in 1970 that resulted in four students being shot and killed by Ohio National Guard troops.

It profiles each of the four students who were killed, telling their stories through the days leading up to May 4th, using personal details gathered through interviews with friends and oral histories from the May 4th special collection and archives amongst other sources.

Derf cites Spain Rodriguez, Mad magazine and Lynda Barry as important influences on his art style.

In 1995, he had a large solo show at Altered Image Gallery in Cleveland, and in 1999 the Akron Art Museum put on a retrospective of his work, titled "Apocalyptic Giggles: The Industrial Cartoon Humor of Derf".

The Billy Ireland Cartoon Library & Museum at the Ohio State University established a Derf Collection of original art and papers in 2011.

[21] In 2021, the Society of Illustrators in New York City held a major exhibition of original art from Kent State: Four Dead in Ohio.