This is the second television series that is based on MAD Magazine. The first was the live-action sketch comedy show "MADtv".
Various animation styles are used, just like its magazine counterpart. The animation in the Spy vs. Spy skits range from ink scribble style, clean Flash animation, and stop-motion.
Some of the animators that worked on the show, went on to create or developed their own series.
Nicole Parker and Debra Wilson, the former 2 cast members of MadTV, had appeared in the show.