AbstractThe invention of general anesthesia (GA) represents a significant advance in modern clinical practices. However, the exact mechanisms of GA are not entirely understood. Because of the multitude of similarities between GA and sleep, one intriguing hypothesis is that anesthesia may engage the sleep‐wake regulation circuits. Here, using fiber photometry and micro‐endoscopic imaging of Ca²⁺ signals at both population and single‐cell levels, it investigates how various anesthetics modulate the neural activity in the ventrolateral preoptic nucleus (vLPO), a brain region essential for the initiation of sleep. It is found that different anesthetics primarily induced suppression of neural activity and tended to recruit a similar group of vLPO neurons; however, each anesthetic caused comparable modulations of both wake‐active and sleep‐active neurons. These results demonstrate that anesthesia creates a different state of neural activity in the vLPO than during natural sleep, suggesting that anesthesia may not engage the same vLPO circuits for sleep generation.