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Background: Duloxetine is a Food and Drug Administration–approved selective norepinephrine reuptake inhibitor for treating depression, anxiety, fibromyalgia, and neuropathic and chronic musculoskeletal pain. This meta-analysis aims to evaluate the efficacy of duloxetine in reducing pain and postoperative opioid use following lower extremity total joint arthroplasty. Methods: A literature search was performed, identifying randomized controlled trials investigating duloxetine for pain management after total hip and total knee arthroplasty. Data from the visual analog scale (VAS) for pain during movement and at rest were extracted for postoperative days (PODs) 1, 3, 7, and 14, as well as postoperative week 6 and postoperative month 3. Opioid use data were obtained at 24, 48 and 72 hours. All data were analyzed using inverse variance with random effects and presented as weighted mean difference. Results: Eight unique studies were identified and included, 7 of which were analyzed quantitatively. Duloxetine decreased postoperative opioid consumption at 48 and 72 hours. For VAS for pain at rest, significantly reduced pain was reported by duloxetine-treated patients at POD 3, POD 7, and postoperative week 6. For VAS for pain at movement, significantly reduced pain was reported by duloxetine-treated patients at POD1, POD 3, POD 7, POD 14, postoperative week 6, and postoperative month 3. Conclusions: Duloxetine appears to decrease postoperative pain and opioid consumption following total joint arthroplasty. However, definitive conclusions are limited by small sample size and study heterogeneity. While there is a need for follow-up studies to determine the optimal dose, duration, and patient population, strong preliminary data provide robust support for future large-scale efficacy studies.