It is widely recognized that sleep loss harms healthy adults. Microglia-mediated synaptic pruning is active during sleep and contributes to memory consolidation. Here, we established a mouse model of sleep deprivation (SD) using a modified multiple-platform method (MMPM). Using western blotting, immunofluorescence, and Golgi-Cox staining, we found that SD increased microglial capacity for phagocytizing mature synapses and decreased the number of mature synapses, which affected long-term memory consolidation but did not affect working memory after SD. Further, we discovered that pretreatment with the APOE mimic peptide COG1410 could partially rescue SD-induced long-term memory consolidation. Regarding the mechanism, COG1410 alleviated SD-induced abnormal microglial phagocytosis and increased the number of mature synapses. Also, COG1410 promoted M2 polarization of microglia and reduced hippocampal inflammation caused by SD. However, whether the anti-inflammatory effect of COG1410 is related to the regulation of microglial phagocytosis still needs further study. Finally, we downregulated the expression of TREM2 in the hippocampus using small interfering RNA (siRNA), which reduced the protective effect of COG1410 in SD mice. In summary, COG1410 has the potential to prevent SD-induced memory consolidation impairment by maintaining microglial phagocytosis and anti-inflammation in the mouse hippocampus.