One hundred twenty patients with chronic lateral ankle instability and preoperative depression were randomized to receive perioperative duloxetine (n=60) or placebo (n=60) starting one day before ATFL repair and continuing for six weeks postoperatively. The primary outcome was postoperative pain intensity and opioid consumption. Secondary outcomes included time to first rescue analgesic, patient satisfaction, functional recovery scores, and adverse effects. Outcomes were assessed at 12, 24, 48, and 72 hours, and at 1, 3, 6, 12, and 24 months postoperatively. Overall, the study found that the duloxetine group experienced significantly lower pain scores, reduced opioid use, longer time to rescue analgesic, and better functional outcomes at 3 and 6 months (p < 0.05), though differences were not significant at 12 and 24 months. Side effects were similar between groups. These findings suggest that perioperative duloxetine improves short-term postoperative pain and functional recovery in patients undergoing ATFL repair.