Glycogen synthase kinase-3β (GSK3β) is a central figure in Wnt signaling, in which its activity is controlled by regulatory binding proteins. Here we show that binding proteins outside the Wnt pathway also control the activity of GSK3β. DNA damage induced by camptothecin, which activates the tumor suppressor p53, was found to activate GSK3β. This activation occurred by a phosphorylation-independent mechanism involving direct binding of GSK3β to p53, which was confined to the nucleus where p53 is localized, and mutated p53 (R175H) bound but did not activate GSK3β. Activation of GSK3 promoted responses to p53 including increases in p21 levels and caspase-3 activity. Thus, after DNA damage there is a direct interaction between p53 and GSK3β, and these proteins act in concert to regulate cellular responses to DNA damage.