In 1983 he worked in a restaurant while he searched for publishers for his comics. He met a waitress who was attending the University of Massachusetts Amherst and followed her to Northampton, Massachusetts. While searching for a local underground newspaper to publish his work, he began a professional relationship with Peter Laird and the two collaborated for a short time on various comics projects.

Eastman purchased his first piece of original artwork ("a couple of pages that were penciled by Michael Golden and inked by Bob McLeod for Marvel Comics' Howard the Duck") at the Atlanta Fantasy Fair, the convention he and Laird attended in 1984. Collecting subsequently became "quite an addiction" for him, and combined with his experiences in getting his, and others', comics work recognised as "Art," led to him founding the Words & Pictures Museum, which operated as a brick-and-mortar museum from 1992–1999.

Their fifth issue of Teenage Mutant Ninja Turtles was released in November 1985, and was downsized to the more Common American comics-format and size. The previous four issues were also reprinted in this size and format with new colored covers. Also in 1985, Solson Publications released How To Draw Eastman and Laird's Teenage Mutant Ninja Turtles. Solson would follow this up with the six issue Teenage Mutant Ninja Turtles Authorized Martial Arts Training Manual as well as one issue of Teenage Mutant Ninja Turtles Teach Karate volume in 1987.

Palladium's role-playing game brought the Turtles to the attention of licensing agent Mark Freedman and the Turtles phenomenon took off, with the various characters soon appearing on T-shirts, Halloween masks, mugs, and other paraphernalia. A five-part televised cartoon mini-series based on the Turtles debuted in December 1987. The half-hour episodes were produced by Osamu Yoshioka and the animation was directed by Yoshikatsu Kasai from scripts David Wise and Patti Howeth. The mini-series was successful, leading to a full series, with the mini-series forming the first season. The series had a 9-year, 10-season, 193-episode run. Bob Burden writes:

In January 1988, Eastman and Laird visited Playmates Toys Inc, who wished to market action figures based on the comic book and animated cartoon series, further cementing the Turtles' place in history and making Eastman and Laird extremely successful.

Eastman founded Tundra Publishing in 1990, to realize personal and other projects. He joined with other comic creators like Scott McCloud and Dave Sim to form the Creator's Bill of Rights. Eastman felt obligated to expand it beyond theory and into practice, providing a forum for comics creators to work for a publisher while maintaining ownership of their work.

Speaking in 1992/93, Eastman was optimistic that the company had "finally reached the point where [it had] slowed up enough... to be giving individual projects the time and attention they require[d];" Shortly thereafter, Tundra was bought out by Kitchen Sink Press, closing its (solo) doors after just three years, losing Eastman between $9 and $14 million.

Eastman has acted in a small number of films, including Guns of El Chupacabra in 1997 and The Rock n' Roll Cops in 2003. He also had a supporting role in the 2004 Troma film Tales from the Crapper. Before that, he had a cameo in the 2000 sequel to The Toxic Avenger called Citizen Toxie: The Toxic Avenger IV. and had a small role in the first TMNT movie as a garbage collector.

On June 1, 2000 Laird and the Mirage Group purchased Eastman's ownership in the Teenage Mutant Ninja Turtles property and corporations. Eastman wanted to move on to other projects. The buyout was completed on March 1, 2008.

Creative differences began to strain Eastman and Laird's partnership. In an interview in 2002, Laird noted that the two hadn't spent much time together since 1993. Eastman moved to California while Laird stayed in Massachusetts.

In 2011, Eastman began working with the TMNT series again as a Writer and Artist on the IDW comic series, as well as an adviser on the 2014 reboot of the Teenage Mutant Ninja Turtles film series. Eastman is said to have a cameo in the film as a Doctor, and has voiced the character Ice Cream Kitty in the 2012 CGI series.

Kevin Eastman has been a longtime fan of the science fiction and fantasy magazine, much of whose content was translated from the French, and appeared in the original Métal Hurlant publication of which Heavy Metal is only the American-licensed incarnation. He cites the publication as bringing Richard Corben to his attention as the "second greatest influence" on him as an Artist, after Jack Kirby. He saw in its pages European art which had not been previously seen in the United States, as well as an underground comix sensibility that nonetheless "wasn't as harsh or extreme as some of the underground comix – but... definitely intended for an older readership."

Eastman sold the magazine to digital and music veteran David Boxenbaum and film Producer Jeff Krelitz in January 2014. Eastman will continue to serve as publisher of the magazine, and is a minority investor in the new Heavy Metal.