PRISMA checklist.

<div> Background Knee osteoarthritis (KOA) is a common degenerative joint disease that primarily affects the elderly individuals. Traditional treatments include medications and physical therapy, but recent attention has turned to platelet-rich plasma (PRP) and hyaluronic acid (HA) injection therapies. Objective This meta-analysis aimed to evaluate the efficacy and safety of PRP combined with HA versus PRP alone in the treatment of KOA. Methods We conducted a comprehensive literature search of the PubMed, Embase, and Cochrane Library databases, which included covering publications from their inception to July 2024. Studies comparing PRP+HA with PRP alone were selected. Data on visual analog scale (VAS) scores, WOMAC total scores, Lequesne scores, and adverse events were extracted. Statistical analysis was performed via Review Manager 5.3.5. Result This meta-analysis included 16 studies involving a total of 1,384 patients. The VAS score comparison indicated that, in the long term, PRP combined with HA was more effective in reducing knee pain than PRP alone was (SMD: -0.30, 95% CI: -0.53 to -0.06, P = 0.01). The combined PRP and HA treatment achieved better results in terms of the WOMAC total score (MD = -6.58, 95% CI: -10.65 to -2.52, P < 0.001). At the 6-month follow-up, the Lequesne index score comparison revealed that PRP combined with HA significantly improved knee pain scores compared with PRP alone (MD = -1.38, 95% CI: -1.91 to -0.86, P < 0.001). In terms of adverse events, PRP+HA was associated with a lower risk of adverse events than PRP alone was (OR = 0.54, 95% CI: 0.33 to 0.85, P = 0.009). Conclusion PRP combined with HA offers significant long-term benefits in pain relief and functional improvement over PRP alone for knee osteoarthritis, with better safety. The sequence of injection may influence treatment outcomes. Systematic review registration PROSPERO <a href="https://www.crd.york.ac.uk/PROSPERO/CRD42024598691" target="_blank">CRD42024598691</a> </div>