Orexin-A and orexin-B neuropeptides are specifically synthesized and secreted in hypothalamic neurons. It is known that the orexinergic system participates in pain modulation as well as its roles in various physiological processes such as feeding, stress processing, endocrine and cognitive functions. Orexin ligands activate orexin type-1 (OXR1) and orexin type-2 (OXR2) receptors, each with a different distribution. Orexins are mediators that play important roles in regulating pain perception at the spinal and supraspinal levels. These regulatory roles of orexins have been demonstrated in mechanical, thermal, and chemical models of pain. Periaqueductal gray (PAG) area of the central nervous system plays an important role in the pain modulation of orexins. Furthermore, the orexinergic system locus seroleus (LC) and paragigantocellular lateralis (LPGi) are associated areas and play an important role in chronic neuropathic pain, stress pain and migraine pain as well as opioid analgesic activity. In addition, it has been expressed that the antinociceptive effects of orexins are mediated by endocannabinoids. This review summarizes studies investigating the antinociceptive effects of orexin in various types of pain, including migraine, neuropathic pain, visceral and orofacial pain, and its effects on opioid analgesia and tolerance.