BACKGROUND: Pain, decreased quality of life, and functional impairment are common symptoms of knee osteoarthritis (KOA), a degenerative joint disease. Surgery is reserved for advanced cases, and conservative treatment is primarily palliative. Although platelet-rich plasma (PRP) therapy is a novel regenerative strategy, the influence of PRP composition on its effectiveness remains unclear. The aim of this review is to determine whether PRP activation and platelet and leukocyte enrichment are associated with improved pain and functional outcomes in KOA at 6 and 12 months. METHODS: The systematic review included 56 randomized controlled trials (RCTs), involving a total of 5251 patients. Of these, 53 RCTs involving 5031 participants were included in the network meta-analysis. PRP treatments were compared with other nonsurgical interventions and placebo. Primary outcomes included Western Ontario and McMaster Universities Arthritis Index Score (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), and visual analog scale (VAS), while International Knee Documentation Committee Score (IKDC), Lequesne Index, and EuroQol (EQ)-VAS were assessed as secondary outcomes. PRP formulations were categorized on the basis of activation status and Mishra's classification system. Both direct and indirect comparisons were performed using a frequentist network meta-analysis approach. RESULTS: Comparing PRP with different activation states at 6 and 12 months revealed that PRP activation exerted significant benefits in specific KOOS domains at 12 months (KOOS Activities of Daily Living, KOOS Sport and Recreation Function, and KOOS Knee-Related Quality of Life). Generally, the performance of high-platelet PRP was not statistically different from that of low-platelet PRP in most of the assisted questionnaires and domains. Considering activated PRP, no significant variation was detected between Mishra's categories, indicating that increased leukocyte and platelet enrichment ratios confer no additional benefit. CONCLUSIONS: Overall, the data suggest that PRP activation could play a key role in the treatment outcomes of KOA and could compensate for variation in both platelet and leukocyte enrichment. There is a need for RCTs to assess the effect of platelet composition and activation status in the clinical performance of PRP in KOA. LEVEL OF EVIDENCE: Level I, systematic review and network meta-analysis.