In 1993, McCracken was tapped by Hanna-Barbera Cartoons to be an art director on the Turner Broadcasting System series 2 Stupid Dogs, where he would also work with Tartakovsky. While at Hanna-Barbera, studio president Fred Seibert began a new project: an animation incubator consisting of 48 new cartoons running approximately seven minutes each. Dubbed What a Cartoon!, it motivated McCracken to further develop his Whoopass Girls! creation, renaming it The Powerpuff Girls in the process. His new pilot, "The Powerpuff Girls in: Meat Fuzzy Lumkins", premiered on February 20, 1995, on Cartoon Network's World Premiere Toon-In, and a second short, "Crime 101", followed on January 28, 1996. The first short to be picked up by the network was Tartakovsky's Dexter's Laboratory, which McCracken would contribute to in early seasons. McCracken's Powerpuff was the fourth cartoon to be greenlit a full series, which premiered on November 18, 1998. The show soon became a hit and has won both Emmy and Annie awards. In 2002 McCracken directed The Powerpuff Girls Movie, a prequel to his series, but it did worse than expected at the box office.
McCracken left The Powerpuff Girls after four seasons, focusing on his next project, Foster's Home for Imaginary Friends. It premiered with the 90-minute television special "House of Bloo's" on August 13, 2004, on Cartoon Network. He developed the series with wife Lauren Faust. The show ran for six seasons, all directed by McCracken, and concluded on May 3, 2009. It also won Emmy and Annie awards.