Pinky (Rob Paulsen) and the Brain (Maurice LaMarche) were Animaniacs characters who became stars of their own series, which debuted the same day as Freakazoid! They had several cameo appearances on Freakazoid!
Harlan Ellison is seen carrying a Pinky and the Brain comic book at a comic convention in "And Fanboy Is His Name."
In "Freakazoid Is History!" Freakazoid witnesses a world altered by his prevention of the 1941 attack on Pearl Harbor. The Brain is President of the United States, and Pinky pilots Air Force One.
The mice appear briefly in reused footage from the Animaniacs main title in "Next Time, Phone Ahead!"
In "The Freakazoid," the Brain shows up randomly to join Freakazoid and Wakko Warner's argument about which cartoon series Steven Spielberg likes best, insisting that "it is the sophisticated wit and charm of Pinky and the Brain that has captured Steven's heart, as well as making it the breakaway hit of the WB's schedule." The three head to Spielberg's conference room at Amblin, all the while fighting over who is Steven's favorite . The three are crushed to learn that Spielberg has no idea who any of them are.
- In "The Freakazoid," Brain yells at Freakazoid, "I don't see your show on the prime time schedule!" From 1995-96, Pinky and the Brain aired Sunday nights on the WB in addition to Saturday mornings. Freakazoid! aired after Pinky and the Brain in prime time for two weeks in June 1996 as a trial run. By the time "The Freakazoid" aired, Pinky and the Brain had been pulled from the prime time lineup.