Mitochondria are essential organelles in neurons providing appropriate energetic needs to maintain resting and action potentials as well as to modulate synaptic plasticity. Although neuronal events underlie various behavioral events, the behavior itself, such as voluntary exercise, feeds back to affect neuronal morphology and function as well as glial morphology and function. The hippocampal formation is a main site of synaptic plasticity induced by voluntary exercise. Here we show that voluntary exercise induces uncoupling protein 2 (UCP2) mRNA expression and mitochondrial oxygen consumption in coupled as well as uncoupled respiratory states in the hippocampus. These changes in mitochondrial metabolism coincided with an increase in mitochondrial number and dendritic spine synapses in granule cells of the dentate gyrus and the stratum radiatum of the CA1 region and were dependent on UCP2 expression, because in UCP2 knock-out mice such changes were not observed. Together, these observations reveal that a mitochondrial mechanism related to UCP2 function is essential for appropriate bioenergetic adaptation of neurons to increased neuronal activity and synaptic plasticity in response to exercise.