This systematic review and meta-analysis included nine randomized controlled trials involving 806 patients undergoing total knee and hip arthroplasty. The study compared perioperative administration of duloxetine to placebo, focusing on outcomes such as visual Analog Scale (VAS) pain scores at rest and during ambulation, postoperative opioid consumption quantified as oral morphine milligram equivalents (MMEs), and the incidence of adverse events. Duloxetine was associated with significant reductions in pain scores at various postoperative time points and in daily opioid MMEs during the first week after surgery. The duloxetine group showed a significantly lower incidence of nausea and vomiting but a significantly higher incidence of drowsiness/somnolence. The analysis suggests that perioperative duloxetine administration can significantly decrease postoperative pain and opioid consumption, with a good safety profile.