The ability to remember and recognize familiar conspecifics is essential for social interaction. Social memory disorders affect normal social interaction. Engram neurons relate to social memory formation with unclear mechanisms. G protein-coupled receptor 50 (GPR50) is an X chromosome-associated orphan receptor and is highly expressed in neurons. In this study, using social disorders mouse model establishing, chemical modulation, electrophysiology, and RNAseq, we herein report a novel role of GPR50 in social memory formation via activating engram neurons. Our results demonstrate that GPR50 upregulation in the excitatory neurons enhances cAMP/p-CREB signaling, which increases the excitability of hippocampal neurons, neuronal firing, and synaptic plasticity, eventually triggering social memory formation. Our study demonstrates a key role of GPR50 in regulating social memory formation.