<p>Platelet-rich plasma (PRP) has emerged as a potential therapeutic approach for hemophilia. Systematically summarize the evidence regarding the efficacy and safety of PRP therapy in hemophilia. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched. Risk of bias was assessed using Cochrane Risk of Bias (RoB 2) and the RoB for Non-Randomized Studies of interventions (ROBINS-I V2). Analyses were conducted separately for hemophilic synovitis and arthropathy given their distinct pathophysiology. A random-effects model was applied for meta-analysis. Evidence certainty was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Six studies were included: 1 randomized controlled trial (RCT) and 5 non-randomized trials. For chronic synovitis, pooled analyses demonstrated significant reductions in Visual Analogue Scale (mean difference: −3.36, − 4.42, and − 2.60 at 3, 6, and 12 months), Hemophilia Joint Health Score (mean difference: −3.00, − 4.72, and − 3.65 at 3, 6, and 12 months); however, all outcomes were rated as very low certainty. For arthropathy, the single high-quality RCT showed no clinically meaningful improvements in Western Ontario and McMaster Universities Osteoarthritis Index, Hemophilia Joint Health Score, Visual Analogue Scale, or magnetic resonance imaging compared with placebo over 24 months (high certainty). Adverse events were minimal, with injection site discomfort reported in 8.4% of patients (high certainty). The evidence for PRP in hemophilic chronic synovitis is of very low certainty, and the results should be interpreted with caution. High-certainty evidence does not support the routine use of PRP in hemophilic arthropathy.</p>