Abstract Background: Diabetic neuropathy is the most common micro-vascular complications of diabetes. The drugs including gabapentin and duloxetine are often used for the treatment of pain associated with diabetic neuropathy. This study aimed to compare the efficacy of duloxetine and gabapentin in the treatment of diabetic peripheral neuropathy. Materials and methods: Totally, 34 patients aged 40 to 70 with diabetic neuropathy were randomly divided into two groups treated with duloxetine and gabapentin and received medical treatment for 45 days. Patients were evaluated for pain before and after treatment using visual analog scale, and also their serum glucose and zinc levels were measured. Results: In both groups statistically significant reduction in mean blood glucose, pain scale, as well as an increase in serum zinc levels at the end of the study was observed compared to baseline. There was no significant difference between the two groups for the mean decrease in blood sugar, but the increase in duloxetine group showed significant improvement compared to gabapentin in increase serum zinc levels and reducing pain. Conclusion: The use of duloxetine in patients with diabetic neuropathic pain is more effective than gabapentin because duloxetine causes a better increase in the serum zinc. Due to the high price of duloxetine in the treatment of diabetic neuropathy, gabapentin administration can be recommended during the first phase of disease and duloxetine can be used in poor and/or insufficient response.