Post-surgical neuropathy is a known complication of many surgical procedures for which few remedies are effective. This study used neurosensory assessments and biochemical assays to evaluate the efficacy of melatonin on nerve healing following orthognathic surgery. Thirty randomly allocated orthognathic patients were prophylactically administered either oral melatonin or identical placebo for 21 consecutive days. Pre- and post-surgical clinical parameters included subjective pain, numbness, and objective neurosensory function. Pre- and post-surgical biochemical parameters were serum hydrogen peroxide and antioxidant enzyme levels. Melatonin was found to significantly reduce subjective pain perception by 50% in the early postoperative days. A 30% reduction in subjective numbness perception was observed at 1-week postoperative, increasing to an over 80% reduction by 3 months postoperative (P<0.00001). Objective neurosensory testing showed a significant improvement in healing profile in the melatonin group. Postoperatively, the hydrogen peroxide concentration was lower in the melatonin group (P<0.00001), and the levels of antioxidant enzymes were higher (P<0.00001). The strong correlations between clinical outcomes and biochemical changes suggest a link between antioxidant effects and reduced postsurgical pain and sensory recovery. The study findings suggest that the prophylactic administration of melatonin confers significant clinical benefits in terms of reduced postoperative pain and opioid use and improved sensory recovery following surgery.