This study investigates the role of microglia in regulating sleep through calcium-dependent modulation of norepinephrine (NE) transmission. Microglia, the resident immune cells in the brain, were found to promote sleep by activating G1-coupled GPCRs, which increases intracellular calcium (Ca2+) levels. This Ca2+ elevation reduces NE transmission, partly by increasing adenosine levels. Chemogenetic activation of microglial G1 signaling increased sleep, while pharmacological blockade of P2Y12 receptors, a G1-coupled receptor, decreased sleep. Two-photon imaging revealed that P2Y12–G1 activation elevated microglial Ca2+ levels, and blocking this elevation abolished the sleep-promoting effect. Additionally, microglial Ca2+ levels increased during natural wake-to-sleep transitions, likely due to reduced NE levels. The study also showed that microglial Ca2+ activity is regulated by sleep-wake states and modulated by NE levels. Overall, the findings suggest that microglia play a crucial role in sleep regulation through reciprocal interactions with NE transmission.This study investigates the role of microglia in regulating sleep through calcium-dependent modulation of norepinephrine (NE) transmission. Microglia, the resident immune cells in the brain, were found to promote sleep by activating G1-coupled GPCRs, which increases intracellular calcium (Ca2+) levels. This Ca2+ elevation reduces NE transmission, partly by increasing adenosine levels. Chemogenetic activation of microglial G1 signaling increased sleep, while pharmacological blockade of P2Y12 receptors, a G1-coupled receptor, decreased sleep. Two-photon imaging revealed that P2Y12–G1 activation elevated microglial Ca2+ levels, and blocking this elevation abolished the sleep-promoting effect. Additionally, microglial Ca2+ levels increased during natural wake-to-sleep transitions, likely due to reduced NE levels. The study also showed that microglial Ca2+ activity is regulated by sleep-wake states and modulated by NE levels. Overall, the findings suggest that microglia play a crucial role in sleep regulation through reciprocal interactions with NE transmission.