Abstract Understanding the neural mechanisms underlying anesthetic-induced unconsciousness remains a central question in both anesthesia research and neuroscience. However, the role of non-neuronal components in modulating anesthetic sensitivity is poorly understood. In this study, we identify a microglia-dependent platelet-derived growth factor subunit B (PDGFB) signaling pathway that modulates propofol anesthesia sensitivity and contributes to the induction of anesthesia in mice. We demonstrate that PDGFB signaling regulates the potassium voltage-gated channel subfamily D member 2 (KCND2) in the hypothalamic paraventricular nucleus (PVN) in mice, thereby orchestrating the excitability of PVN glutamatergic neurons (PVN Glu) and the activity of their projections to lateral hypothalamic glutamatergic neurons (LH Glu). Microglia deprivation induces PDGFB deficiency and downregulates KCND2, resulting in PVN hyperexcitability and hyperactivation of the PVN → LH arousal circuit, which contributes to resistance to anesthesia induction in mice. Our findings identified non-neuronal molecular mechanism that governs anesthetic sensitivity, complementing the classical γ-aminobutyric acid type A receptor-centric model and providing insights into the regulation of anesthesia induction.