Background: Platelet-rich plasma (PRP) and hyaluronic acid (HA) are non-surgical treatments for osteoarthritis (OA), but the comparison of their efficiency is still inconclusive. Objectives: The objectives of this study were to compare the efficacy of PRP and HA in the treatment of OA by meta-analysis and to explore the effects of different injection times and leukocyte concentration on the efficacy of PRP. Design: Meta-analysis and subgroup analysis were conducted. The data were analyzed by Review Manager v5.4.1. Data sources and methods: Articles were retrieved and screened from PubMed, the Cochrane Library, Web of Science, and Embase. The outcome included the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the visual analog scale (VAS), adverse events (AEs), the International Knee Documentation Committee (IKDC), and the satisfaction rate. Results: A total of 30 articles involving 2733 patients were included. The total WOMAC score and IKDC score of the PRP group were better than those of the HA group at the last follow-up time, while there was no significant difference in AEs, satisfaction rate, and VAS between the two groups. In our subgroup analysis, there was no significant difference between single-injection PRP and triple-injection PRP. Leukocyte-poor PRP (LP-PRP) was better than leukocyte-rich PRP (LR-PRP) in IKDC, but there was no significant difference between them in the other scores. Conclusions: In the treatment of OA, compared with HA, PRP performed better in the improvement of the patient’s function. There was no significant difference in VAS and AEs between the two groups, and the safety was comparable. LP-PRP looked to be superior to LR-PRP in functional recovery, but there appeared to be no significant difference in pain relief between them. There was no significant difference between single PRP and triple PRP in the subgroup analysis.