Osteoarthritis (OA) is the most common form of arthritis, affecting approximately 15% of the population. The aim of this study was to evaluate the efficacy of sesame oil in controlling OA pain in rats. Rat joint pain was induced by medial meniscal transection in Sprague–Dawley rats and assessed by using hindlimb weight distribution method. Muscular oxidative stress was assessed by determining lipid peroxidation, reactive oxygen species and circulating antioxidants. Sesame oil significantly decreased joint pain compared with positive control group in a dose-dependent manner. Sesame oil decreased lipid peroxidation in muscle but not in serum. Further, sesame oil significantly decreased muscular superoxide anion and peroxynitrite generations but increased muscular glutathione and glutathione peroxidase levels. Further, sesame oil significantly increased nuclear factor erythroid-2-related factor (Nrf2) expression compared with positive control group. We concluded that daily sesame oil supplement may attenuate early joint pain by inhibiting Nrf2-associated muscular oxidative stress in OA rat model.