Background: Chronic pain treatment until now is still challenging because of its complex pathopgysiology. Previously, red ginger oil (RGO) reduced pain behavior in a mouse model of chronic pain, but the mechanisms were unclear. Objectives: This study examined the effect of RGO on cyclooxygenase (COX)-2 and the N-methyl-D-aspartate receptor (NMDAR) using inflammatory- or neuropathy-induced chronic pain in mice. Methods: Red ginger was distilled with composition 1:2 using water. The acute toxicity of RGO was evaluated using OECD guidelines 423. Chronic pain was induced in 48 mice by either (1) intraplantar injection of complete Freund’s adjuvant (CFA) (inflammatory group) or (2) partial sciatic nerve ligation (PSNL) (neuropathy group). After seven days, mice were randomly divided into sham, CFA/PSNL, or RGO (at doses of 100, 200, 400, or 600 mg/kg) treatment groups. Treatments were given orally once daily until day 14. On day 15, mice were euthanized, and the brains and spinal cords were removed and fixed in 10% formalin. Hyperalgesia behavior was evaluated using hot plate test. Spinal cord morphology was analyzed via hematoxylin and eosin staining. COX-2 and NMDAR expressions were evaluated by immunohistochemistry. Results: RGO treatment improved spinal cord morphology after the induction of chronic pain. RGO at 600 mg/kg also reduced COX-2 expression in the spinal cord and brain, and reduced NMDAR2B in the spinal cord. However, RGO at 600 mg/kg increased NMDAR2A expression in the spinal cord. Conclusions: RGO administration diminished hyperalgesia in chronic pain models through inhibition of COX-2 and NMDAR2B.