Eleven randomized controlled trials (RCTs) including 1023 patients with knee osteoarthritis (KOA) were analyzed in this systematic review and meta-analysis to compare PRP + HA combination therapy versus PRP monotherapy. The pooled outcomes assessed included changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total scores, Visual Analogue Scale (VAS) scores, Lequesne index scores, International Knee Documentation Committee (IKDC) scores, and adverse events. PRP + HA showed significant superiority over PRP alone in reducing WOMAC scores, VAS scores, and Lequesne index scores, while increasing IKDC scores and demonstrating a lower risk of adverse events. These findings suggest that PRP + HA therapy is both safe and more effective in pain relief and functional improvement than PRP alone.