Fighting for the first time since losing the heavyweight title to Cain Velasquez 14 months ago, Lesnar was dropped by a body kick to the liver and Overeem pounced for the finish with punches on the ground.
Lesnar, a former WWE superstar and NCAA wrestling champion, ends his MMA career at 5-3. After suffering a first-round submission to Frank Mir in his Octagon debut in 2008, Lesnar rebounded with a win over Heath Herring and claimed the UFC title in his next fight with a knockout of Randy Couture.
Lesnar defended the title over Frank Mir and Shane Carwin, but was sidelined twice for extended periods by diverticulitis, which culminated in surgery to have a foot of his colon removed earlier this year.
More UFC 141 coverage: