Mitochondrial fission and trafficking to dendritic protrusions have been implicated in dendritic spine development. Here, we show that Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1) controls depolarization-induced mitochondrial movement into dendritic spines and filopodia and regulates spine morphogenesis. Depolarization-induced degradation of the p35 regulatory subunit of cyclin-dependent kinase 5 (Cdk5), with the resultant decreased inhibitory phosphorylation on WAVE1, depend on NMDA receptor activation. Thus, WAVE1 dephosphorylation and activation are likely associated with mitochondrial redistribution and spine morphogenesis.