When disgraced Harvard philosophy scholar Jack Griffin loses out on his dream job, he is forced to return to Toledo, Ohio, and work as a high school Advanced Placement biology teacher.

Megamind's former villain team, The Doom Syndicate, has returned. Our newly crowned blue hero must now keep up evil appearances until he can assemble his friends (Roxanne, Ol' Chum and Keiko) to stop his former evil teammates from launching Metro City to the Moon.