Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission. This study shows that microglia in mice regulate sleep via G protein-coupled GPCRs, intracellular calcium signaling, and suppression of norepinephrine (NE) transmission. Chemogenetic activation of microglial G protein signaling promotes sleep, while pharmacological blockade of GPCRs like P2Y12 receptors decreases sleep. Two-photon imaging revealed that P2Y12-Gi activation increases microglial intracellular calcium, which is linked to sleep promotion. Microglial calcium levels naturally rise during sleep due to reduced NE levels. Activation of P2Y12-Gi signaling reduces NE levels, partly by increasing adenosine. These findings indicate that microglia regulate sleep through reciprocal interactions with NE transmission. Microglia, as the brain's resident immune cells, play a key role in brain homeostasis, including neuronal activity modulation and clearance of metabolic waste. Sleep disturbances and microglial dysfunction are linked to neurodegenerative diseases. This study highlights the role of microglia in sleep regulation, showing that their calcium signaling and NE transmission are interconnected. The findings suggest that microglia contribute to sleep regulation by modulating NE levels, which in turn affects brain homeostasis. The study also shows that microglial calcium activity is influenced by brain states, with higher activity during sleep. The results provide a mechanistic understanding of how microglia regulate sleep through calcium and NE signaling, offering insights into the complex interactions between the immune system and sleep.Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission. This study shows that microglia in mice regulate sleep via G protein-coupled GPCRs, intracellular calcium signaling, and suppression of norepinephrine (NE) transmission. Chemogenetic activation of microglial G protein signaling promotes sleep, while pharmacological blockade of GPCRs like P2Y12 receptors decreases sleep. Two-photon imaging revealed that P2Y12-Gi activation increases microglial intracellular calcium, which is linked to sleep promotion. Microglial calcium levels naturally rise during sleep due to reduced NE levels. Activation of P2Y12-Gi signaling reduces NE levels, partly by increasing adenosine. These findings indicate that microglia regulate sleep through reciprocal interactions with NE transmission. Microglia, as the brain's resident immune cells, play a key role in brain homeostasis, including neuronal activity modulation and clearance of metabolic waste. Sleep disturbances and microglial dysfunction are linked to neurodegenerative diseases. This study highlights the role of microglia in sleep regulation, showing that their calcium signaling and NE transmission are interconnected. The findings suggest that microglia contribute to sleep regulation by modulating NE levels, which in turn affects brain homeostasis. The study also shows that microglial calcium activity is influenced by brain states, with higher activity during sleep. The results provide a mechanistic understanding of how microglia regulate sleep through calcium and NE signaling, offering insights into the complex interactions between the immune system and sleep.