Cortical spreading depolarizations are an epiphenomenon of human brain pathologies and associated with extensive but transient changes in ion homeostasis, metabolism, and blood flow. Previously, we have shown that cortical spreading depolarization have long-lasting consequences on the brains transcriptome and structure. In particular, we found that cortical spreading depolarization stimulate hippocampal cell proliferation resulting in a sustained increase in adult neurogenesis. Since the hippocampus is responsible for explicit memory and adult-born dentate granule neurons contribute to this function, cortical spreading depolarization might influence hippocampus-dependent cognition. To address this question, we induced cortical spreading depolarization in C57Bl/6J mice by epidural application of 1.5mol/L KCl and evaluated neurogenesis and behavior at two, four, or six weeks thereafter. Congruent with our previous findings in rats, we found that cortical spreading depolarization increases numbers of newborn dentate granule neurons. Moreover, exploratory behavior and object location memory were consistently enhanced. Reference memory in the water maze was virtually unaffected, whereas memory formation in the Barnes maze was impaired with a delay of two weeks and facilitated after four weeks. These data show that cortical spreading depolarization produces lasting changes in psychomotor behavior and complex, delay- and task-dependent changes in spatial memory, and suggest that cortical spreading depolarization-like events affect the emotional and cognitive outcomes of associated brain pathologies.