Neuropeptide S (NPS) is an endogenous peptide that regulates various physiological functions, such as immune functions, anxiety-like behaviors, learning and memory, the sleep–wake rhythm, ingestion, energy balance, and drug addiction. These processes include the NPS receptor (NPSR1). The NPS–NPSR1 system is also significantly associated with the onset of disease, as well as these physiologic functions. For example, NPS is involved in bronchial asthma, anxiety and awakening disorders, and rheumatoid arthritis. In this review, among the various functions, we focus on the role of NPS in anesthesia-induced loss of consciousness; analgesia, mainly by anesthesia; and sleep–wakefulness. Progress in the field regarding the functions of endogenous peptides in the brain, including NPS, suggests that these three domains share common mechanisms. Further NPS research will help to elucidate in detail how these three domains interact with each other in their functions, and may contribute to improving the quality of medical care.