BACKGROUND AND PURPOSE Postoperative pain is one of the most common manifestations of acute pain and is an important problem faced by patients after surgery. Moreover, neuronal trauma or chemotherapeutic treatment often causes neuropathic pain, which induces disabling and distressing symptoms. At present, treatments of both painful conditions are inadequate. α-Spinasterol, which is well characterized as a transient receptor potential vanilloid 1 antagonist, has anti-inflammatory, antioxidant and antinociceptive effects. Therefore, we investigated its antinociceptive potential on postoperative and neuropathic pain, as well as its effect on COX-1 and COX-2 activities. EXPERIMENTAL APPROACH Nociceptive responses in a postoperative pain model (surgical incision-induced) or different neuropathic pain models (trauma or chemotherapy-induced) were investigated in mice. KEY RESULTS Oral administration of α-spinasterol reduced postoperative pain, when given as a pre- (0.5 h before incision) or post-treatment (0.5 h after incision), and reduced cell infiltration in the injured tissue. α-Spinasterol also reduced the mechanical allodynia induced by partial sciatic nerve ligation and the mechanical and cold allodynia induced by paclitaxel. Moreover, α-spinasterol inhibited COX-1 and COX-2 enzyme activities without altering the body temperature of animals. Importantly, α-spinasterol did not alter spontaneous or forced locomotor activity. Furthermore, it did not cause gastric damage or liver and kidney changes, nor did it alter cell viability in the cerebral cortex and spinal cord slices of mice. CONCLUSION AND IMPLICATIONS α-Spinasterol is an effective and safe COX inhibitor with antinociceptive effects in postoperative and neuropathic pain models. Therefore, it is an interesting prototype for the development of novel analgesic drugs.