Much progress has been made in the understanding of the neural circuits associated with sleep and anesthesia. As an important component among these circuits, the forebrain nuclei have been frequently interrogated. This study demonstrates that glutamatergic (Glu) neurons in the ventral pallidum (VP) enhance activity upon salient stimuli and state-dependently modulate brain arousal and motor activity in freely behaving male mice, and bidirectionally regulate the induction of and emergence from isoflurane general anesthesia. We delineate a neural pathway, consisting of VP Glu neurons→ noradrenergic (NA) neurons in the locus coeruleus (LC)→the lateral hypothalamus (LH) in male mice, controlling the release of noradrenaline in the LH and state-dependently modulated brain arousal, motor activity, and isoflurane general anesthesia through α2a receptors in the LH. Therefore, the VP-LC-LH pathway and α2a receptors in the LH may be promising state-dependent regulators of brain arousal in both freely behaving and anesthetized states.