Willingham got his start in the late 1970s to early 1980s as a staff artist for TSR, Inc., where he illustrated a number of their role-playing game products. He was the cover artist for the AD&D Player Character Record Sheets, Against the Giants, Secret of Bone Hill, the Gamma World book Legion of Gold, and provided the back cover for In the Dungeons of the Slave Lords. He was an interior artist on White Plume Mountain, Slave Pits of the Undercity, Ghost Tower of Inverness, Secret of the Slavers Stockade, Secret of Bone Hill, Palace of the Silver Princess, Isle of Dread, In the Dungeons of the Slave Lords, the original Fiend Folio, Descent into the Depths of the Earth, Assault on the Aerie of the Slave Lords, Against the Giants, Queen of the Spiders, Realms of Horror, and the second and third editions of Top Secret.
He first gained attention for his 1980s comic book series Elementals published by Comico, which he both wrote and drew, however the series had trouble maintaining a consistent schedule, and Willingham's position in the industry remained spotty for many years. He contributed stories to Green Lantern and started his own independent, black-and-white comic book series Coventry which lasted only 3 issues. He also produced the pornographic series Ironwood for Eros Comix.
In the late 1990s, Willingham reestablished himself as a prolific writer. He produced the 13-issue Pantheon for Lone Star Press and wrote a pair of short novels about the modern adventures of the hero Beowulf, and a fantasy novel Down the Mysterly River published by the Austin, Texas writer's collective, Clockwork Storybook, of which Willingham was a founding member. In the early 2000s, he began writing extensively for DC Comics, including the limited series Proposition Player, a pair of limited series about the Greek witch Thessaly from The Sandman, and most notably the popular series Fables.
Willingham worked on the Robin series from 2004 to 2006, and established Shadowpact, a title spun off his Day of Vengeance limited series. He is currently writing Jack of Fables, an ongoing spin-off of his Fables series, co-written by Matthew Sturges. At the 2007 Comic Con International, he announced that he would be writing Salvation Run, a mini-series about supervillains who are banished to an inhospitable prison planet. Unfortunately, he had to hand over the writing to Sturges after two issues because of illness. He will also be working on Decisions, a four-issue mini-series that deals with Green Arrow's endorsement of a political candidate and, again with Sturges, is writing the Vertigo series House of Mystery and DC's Justice Society of America with issue #29.
In 2009, Willingham agreed to write for Angel by IDW Publishing, kicking off a new storyline titled "Immortality for Dummies."