The management of diabetic neuropathy (DN) is still a challenge for physicians. Hyperglycemia induced oxidative stress involves in the development of diabetic neuropathy, which could be reversed by supplementation of antioxidants. In the present study, it has targeted the oxidative stress mediated nerve damage in DN by using combined therapy of rutin (RT) and silymarin (SM). Diabetes was induced by single streptozotocin (STZ, 65 mg/kg i.p.) injection. The diabetic rats were treated daily with RT (100 mg/kg), SM (60 mg/kg) and RT (50 mg/kg) + SM (30 mg/kg) for 6 consecutive weeks. Pain-related behavior tests were performed including tail flick, paw-pressure analgesia and Rota-rod treadmill performance. Serum glucose, insulin, tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6) and interleukine-1β (IL-β) levels were estimated. Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels and enzymatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) were measured. Diabetic rats that developed neuropathy were revealed by decreased tail-flick latency, paw-withdrawal latency and motor coordination. RT (100 mg/kg/day) and SM (60 mg/kg/day) dosed to diabetic rats, ameliorated hyperalgesia, analgesia and led to improved motor coordination. However, the combined therapy of RT (50 mg/kg/day) with SM (30 mg/kg/day) showed more significant effects in these parameters. STZ significantly increased TBARS and decreased GSH levels in sciatic nerve whereas combined therapy of RT and SM produced higher significant protection compared to individual. Similarly, combined therapy showed more significant amelioration in decreased levels of SOD, CAT, GST, GS and GPx activities in sciatic nerve of diabetic rats. Present results concluded that the combined therapy of phenolic compounds such as RT and SM had higher protective effects than their individual supplementations against DM.