TenNapel began as an animator on Attack of the Killer Tomatoes: The Animated Series. He soon began working in the video game industry on projects like 1993’s Jurassic Park and The Ren & Stimpy Show: Stimpy’s Invention for the Sega Genesis and The Jungle Book for the SNES and Sega Genesis. In 1994, he created Earthworm Jim, the character that would star in Shiny Entertainment’s video game, toy line, and cartoon series. Shiny Entertainment head David Perry later commented on working with TenNapel, “I wish I could find 100 Dougs, then I realized I was lucky to have been able to work with one. He is crazy talented, both crazy and talented! He also generates an enormous amount of amazing content and ideas, I wouldn’t be surprised if he sleeps with a sketch-book!” In 1995, he left Shiny Entertainment and founded his own company, Neverhood, with several other former Shiny employees. Working for DreamWorks Interactive, Neverhood created The Neverhood for the PC and PlayStation. The sequel, entitled Skullmonkeys, followed in 1998.

Flink, a graphic novel by TenNapel, was released in late 2007 through Image Comics. Monster Zoo, was released in early summer 2008. In May 2009 his graphic novel Power Up was released.

In July 2010, his graphic novel Ghostopolis was released. In 2009, it was announced the book would be adapted into a film starring and produced by Hugh Jackman, but no update has been given since then.

In September 2012, Fox Animation optioned TenNapel’s published Graphix novel Cardboard, with plans for actor Tobey Maguire’s Material Pictures, graphic novelist Doug TenNapel, and the Gotham Group to be executive producers. Fox planned to have the picture developed under its WedgeWorks subsidiary. WedgeWorks director Chris Wedge (Ice Age) was producing, and considered directing the film as well. As of 2020, no update has been given on the film, especially given the acquisition of 21st Century Fox assets by The Walt Disney Company.

TenNapel and other former members of the Earthworm Jim team at Pencil Test Studios launched a Kickstarter campaign in May 2013 to fund a PC game project called Armikrog, described a spiritual successor to The Neverhood and also being animated using clay animation techniques. It was successful, and reached its stretch goal for a Wii U version.

In 2018, TenNapel self-published the graphic novel, Bigfoot Bill, launched as an Indiegogo, successfully funded and reaching various stretch goals.

In May 2019, TenNapel and other members of the original Earthworm Jim team announced a new Earthworm Jim game, to be released as an exclusive for the upcoming Intellivision Amico. He also self-published the graphic novel, Earthworm Jim: Launch the Cow, again on Indiegogo. As of August 2019, Earthworm Jim: Launch the Cow is the second-highest-grossing crowd-funded comic book of all time (US$816,000), trailing only The Order of the Stick Reprint on Kickstarter ($1.2 million), and overtaking the comic book anthology Ctrl+Alt+Del (US$665,000).