5-hydroxytryptamine (5-HT), a crucial neurotransmitter, regulates several vital physiological processes, including the sleep-wake cycle. Given the similarities between the transition from natural sleep to wake and the transition from anesthesia-induced unconsciousness to recovery from anesthesia, recent researches have increasingly focused on elucidating the link between the 5-HTergic system and the mechanisms of general anesthesia. This paper reviews the mechanisms of 5-HTergic nervous system interaction with other nervous systems in modulating arousal from general anesthesia and the differential modulatory effects mediated by distinct 5-HT receptor subtypes. Furthermore, by combining current research advances, this paper provides an outlook on the clinical translational potential of modulating the 5-HTergic system to promote arousal from general anesthesia, aiming to provide a theoretical basis for experimental research on the mechanism of arousal from anesthesia and clinical application of perioperative management.