Growing up in Boston, Ryan studied English Literature at the University of Massachusetts at Amherst.

Ryan originally self-published Angry Youth Comix, producing ten mini-comic issues from 1994 to 1998. In 1998, he began showing his work to Peter Bagge, creator of Hate comics, who introduced the material to Eric Reynolds of Fantagraphics. In 2001, Fantagraphics began publishing volume 2 of the series.

Collaborating with Dave Cooper under the pen name "Hector Mumbly", Ryan's comics appeared in nearly every issue of Nickelodeon Magazine. Cooper and Ryan also collaborated on a "Wonder Woman vs. Supergirl" story for the DC Comics anthology Bizarro. Ryan collaborated with Peter Bagge in both Angry Youth Comix and Bagge's Hate Annual, in addition to penciling and inking two stories for Bagge's DC series Sweatshop. In 2006, Ryan guest-edited a special comics issue of Vice magazine, which included contributions from over thirty of Ryan's comics contemporaries.

Ryan's illustrations have appeared in MAD, LA Weekly, National Geographic Kids, Hustler Magazine, The Stranger, and elsewhere. Ryan has also done work for clients such as Nobleworks greetings cards, Rhino Records, and FOX television.

His comics have been translated into Spanish and Portuguese.

Ryan lives in Los Angeles with his wife.

Angry Youth Comix was nominated for a Best Mini Ignatz Award at the 2000 Small Press Expo. It has since been nominated for multiple Harvey and Eisner Awards.