Eighty-four patients with primary knee osteoarthritis were randomized to receive duloxetine 30 mg daily for 6 weeks (n=42) or standard multimodal analgesia alone (n=42). The primary outcome was VAS pain at rest, during walking, and at night at 24 h, 72 h, 2 weeks, 6 weeks, and 12 weeks. Secondary outcomes were morphine use (0–72 h), adverse events, knee ROM, and function (OKS, KOOS). Overall, the results of the study revealed no between-group differences in VAS at rest or during walking at any timepoint, with a single improvement for night pain at 2 weeks in the duloxetine group; total morphine consumption over 72 h was ~33% lower with duloxetine, and KOOS “symptoms” scores were better at 6 and 12 weeks, with similar adverse events and ROM. In short, low-dose duloxetine did not meaningfully lower early pain scores but did reduce opioid use and modestly improved symptom scores, supporting its consideration as an adjunct to multimodal analgesia after TKA.