Learning and memory require orchestrated regulation of both structural and functional synaptic plasticity in the hippocampus. While a neuropeptide alpha-melanocyte-stimulating hormone, α-MSH, has been implicated in memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in hippocampal-dependent synaptic plasticity has not been explored. In this study, we report that activation of MC4R enhances synaptic plasticity through the regulation of dendritic spine morphology and abundance of AMPA receptors. We show that activation of postsynaptic MC4R increases the number of mature dendritic spines and enhances surface expression of AMPA receptor subunit GluA1, resulting in synaptic accumulation of GluA1-containing AMPA receptors. Moreover, MC4R stimulates surface GluA1 trafficking through phosphorylation of GluA1 at Ser845 in a Gα(s)-cAMP/PKA-dependent manner. Blockade of protein kinase A (PKA) signaling abolishes the MC4R-mediated enhancement of neurotransmission and hippocampal long-term potentiation. Importantly, in vivo application of MC4R agonists increases LTP in the mouse hippocampal CA1 region. These findings reveal that MC4R in the hippocampus plays a critical role in the regulation of structural and functional plasticity.