BACKGROUND: Postoperative pain management is essential for patient satisfaction; however, no reports have described the effect of perioperative duloxetine administration on the postoperative pain management following knee surgery. This study aimed to determine whether perioperative duloxetine administration reduces pain following high tibial osteotomy. METHODS: In this prospective clinical trial, 35 and 33 patients receiving (40 mg/day) and not receiving duloxetine (control), respectively were enrolled. The knee pain and quality of recovery were evaluated using the numeric rating scale (NRS) scores, the frequency of analgesic drugs used, and patient-reported outcome measures, including the NRS score at rest and the Knee Injury and Osteoarthritis Outcome Score (KOOS), were compared between the groups. RESULTS: The NRS scores of the duloxetine group (D) were significantly reduced compared with those of the control group (C) on postoperative day 1 (D:3.8 vs C:5.1, p = 0.022), day 7 (D:2.1 vs C:2.9, p = 0.021), and day 14 (D:1.6 vs C:2.9, p = 0.001). Non-steroidal anti-inflammatory drug administration was significantly lower in the duloxetine group than in the control group (p < 0.001). Although the KOOS score was not significantly different in several subcategories at the pre- and postoperative time-points, the Function in Sport subcategory of the KOOS was significantly improved in the duloxetine group compared with that in the control group at 3 months postoperatively (p < 0.05). CONCLUSION: Perioperative use of duloxetine from 2 weeks before surgery to 2 weeks after surgery is advantageous in perioperative pain management and KOOS improvement following high tibial osteotomy.