Sleep is essential for memory formation and consolidation, and sleep loss is associated with cognitive decline. The CA2 subregion of the hippocampus is involved in social memory and plays a critical role in altering brain activity and memory performance. Despite the crucial role of hippocampal CA2 in memory, how sleep influences social memory remains relatively unexplored. Our aim was to investigate whether and how sleep loss influences the CA2 region in terms of synaptic plasticity and social memory in mice. We conducted field electrophysiology, Western blot analysis, and behavioral studies. We found that 5-hour sleep deprivation impaired long-term potentiation in the hippocampal CA2 region with an increased expression of adenosine type 1 receptor. Additionally, caffeine-induced synaptic potentiation in the CA2 subregion decreased after sleep loss. Consistent with deficits in long-term synaptic plasticity in the hippocampal CA2 region, sleep-deprived mice exhibited impairments in social memory, failing to recognize novel mice from familiar ones in the social recognition memory test. The expression of several proteins such as PKMζ, ERK, and BDNF, which are important for long-term plasticity, was found to be reduced in the CA2 subregion after sleep deprivation. Thus, the disruption in the hippocampal CA2 area could play a causal role in social memory deficits resulting from sleep loss in mice. Our findings underscore the impact of sleep deprivation on CA2 synaptic plasticity and emphasize the importance of sleep modulation as a promising future therapeutic approach.