Beginning in 1980, Foglio wrote and illustrated the comic strip What's New with Phil & Dixie for Dragon Magazine from TSR Games, satirizing the world of role-playing games. The strip ran monthly for three years. In the early 1980s, after some time in Chicago attempting to find work doing science fiction magazine and book illustration, Foglio moved to New York City. He formed the independent comic-book company fantasy factory with science-fiction writer-artist Freff and SF book editor Melissa Ann Singer. Working with editorial input from Chris Claremont, Foglio and Freff wrote and drew a single issue of a science-fiction/historical title called D'Arc Tangent before ending their collaboration in 1984.
He eventually returned to the Rogers Park neighborhood of Chicago, and continued fantasy and science fiction art. For publisher Donning/Starblaze, Foglio illustrated the MythAdventures series of fantasy novels by Robert Lynn Asprin, and later adapted the first book, Another Fine Myth, into an eight-issue comic-book series from WaRP Graphics. The WaRP work eventually led to comic-book assignments from DC Comics (Angel and the Ape, Plastic Man and Stanley and His Monster miniseries), Marvel Comics, and First Comics (issues of GrimJack and Dynamo Joe.) He also joined the Moebius theatre group, and held regular meetings and poker parties for the local science fiction community.
Foglio initiated his long-running character Buck Godot for the publication Just Imagine, published by Denny Misinger. Basing the humorous science-fiction detective on a real-life friend, John Buckley, Foglio "did a couple of those in the black-and-whites and then Donning said they wanted Buck Godot graphic novels", two of which followed.
In the 1990s, Foglio met and married his wife, Kaja. The two contributed art to the collectible card game Magic: The Gathering, from Wizards of the Coast, and resurrected the comic strip What's New? for that company's Duelist magazine. During this decade, Foglio co-founded Palliard Press and published additional comics, including a new Buck Godot series and the whimsical erotic series XXXenophile. The Foglios later founded Studio Foglio and began to produce the retro-fantasy series Girl Genius.
In April 2005, the Foglios abandoned publishing periodical-style comic books and began publishing Girl Genius online as a free webcomic, updated three times a week. Foglio told an interviewer that as of November 2005, "[W]e've quadrupled our number of readers, and tripled our sales" of traditional comics and related merchandise.
He has been nominated for Best Professional Artist in 2008.