Despite its critical importance to social animals, the mechanisms underlying the establishment of new social interactions remain largely unknown. We identified a role for neurons expressing neuropeptide B/W receptor-1 (NPBWR1) in the central amygdala (CeANpbwr1 neurons) in this process. CeANpbwr1 neurons were activated only during physical interactions with unfamiliar mice, but not with familiar mice. Manipulations of the neuronal circuit comprising CeANpbwr1 neurons suggested that this excitation was essential for sustaining physical interactions with novel conspecifics. Remarkably, stimulating CeANpbwr1 neurons effectively reversed sociability deficits induced by chronic social defeat stress. Conversely, overexpressing human NPBWR1 in CeANpbwr1 neurons, which reduced CeANpbwr1 neuronal activity, led to decreased social interaction with unfamiliar conspecifics. In contrast, the human NPBWR1 gene with a single nucleotide polymorphism (404A>T) did not show this effect. These findings demonstrate that CeANpbwr1 neurons maintain social novelty preference, while NPBWR1 counters this function. Moreover, polymorphisms found in NPBWR1 may play a role in shaping an individual's characteristics when interacting with unfamiliar individuals.