Insufficient sleep is a global problem with serious consequences for cognition and mental health.¹ Synapses play a central role in many aspects of cognition, including the crucial function of memory consolidation during sleep.² Interference with the normal expression or function of synapse proteins is a cause of cognitive, mood, and other behavioral problems in over 130 brain disorders.³ Sleep deprivation (SD) has also been reported to alter synapse protein composition and synapse number, although with conflicting results.^4,5,6,7 In our study, we conducted synaptome mapping of excitatory synapses in 125 regions of the mouse brain and found that sleep deprivation selectively reduces synapse diversity in the cortex and in the CA1 region of the hippocampus. Sleep deprivation targeted specific types and subtypes of excitatory synapses while maintaining total synapse density (synapse number/area). Synapse subtypes with longer protein lifetimes exhibited resilience to sleep deprivation, similar to observations in aging and genetic perturbations. Moreover, the altered synaptome architecture affected the responses to neural oscillations, suggesting that sleep plays a vital role in preserving cognitive function by maintaining the brain's synaptome architecture.