Sleep deprivation (SD) has been recognized as a pivotal factor exacerbating the risk of psychiatric disorders; however, the neurobiological mechanisms underlying SD-induced alterations in brain network structure cannot be fully explained by monoaminergic neurotransmitter imbalances alone. This review systematically elucidates the “sleep-microglia-synaptic remodeling” axis as a core pathological mechanism, proposing that SD disrupts central nervous system homeostasis and induces a phenotypic transition of microglia from physiological synaptic sentinels to pathological agents of excessive phagocytosis. At the molecular level, SD promotes the “over-pruning” of functional synapses by aberrantly reactivating developmental signaling pathways in the adult brain—specifically the complement component 3–complement receptor 3 (C3–CR3), adenosine triphosphate–P2Y12 receptor signaling (ATP–P2Y12), and astrocyte-microglia crosstalk. This process results in a reduced synaptic density and impaired structural plasticity. Such neuroimmune-mediated synaptic pathology constitutes a shared anatomical substrate for the cognitive and emotional deficits observed in major psychiatric conditions, including major depressive disorder, schizophrenia, and anxiety disorders. In summary, dissecting this mechanism not only offers a novel perspective on the comorbidity of sleep disturbances and psychiatric disorders but also highlights that targeting the blockade of pathological microglial phagocytic pathways serves as a promising therapeutic strategy for restoring synaptic homeostasis and treating psychiatric diseases.