One hundred fifty patients with knee osteoarthritis were randomized to receive either oral duloxetine combined with an intraarticular injection of corticosteroid plus hyaluronic acid (n=75) or an intraarticular injection alone (n=75). The primary outcome of interest was the change in the weekly 24-hour average mean pain scores. Secondary outcomes included the proportion of patients with ≥ 30% or ≥ 50% pain reduction, Brief Pain Inventory (BPI) scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, Patient Global Impression Improvement (PGI-I) ratings, hospital anxiety and depression scale (HADS) scores, and adverse events (AEs). Outcomes were assessed at multiple time points over a 24-week period. Overall, the results revealed that the group receiving the combination therapy had significantly better pain reduction and knee function improvement than the group receiving the injection alone. This suggests that co-treatment with duloxetine and an intraarticular injection may offer a more effective approach to managing knee osteoarthritis pain.