Objective: To asses the clinical efficacy of platelet-rich plasma (PRP) for knee osteoarthritis (KOA), explore its mechanism of action based on inflammation and matrix metabolism regulation, and analyze the impact of PRP quality parameter heterogeneity on therapeutic outcomes. Methods: 80 patients with KOA in the Department of Orthopedics and Pain Medicine at Shijiazhuang People''s Hospital from July 2022 to October 2024 were selected. The 80 KOA patients were randomly divided into a hyaluronic acid (HA) group (n=40) and a platelet-rich plasma (PRP) group (n=40) using a random number generation method. The PRP group received intra-articular injection of PRP into the knee joint cavity once weekly for a total of 3 sessions, while the HA group received intra-articular injection of HA into the knee joint cavity once weekly for a total of 3 sessions. The visual analog scale (VAS) for pain and the Western Ontario and Montreal Arthritis Clinic (WOMAC) score were compared between the two groups before treatment and at 1 month, 3 months, and 6 months post-treatment. Inflammatory cytokines (IL-1β, TNF-α, IL-6) and key proteins of the NF-κB pathway (p-p65, IκBα) in synovial fluid were measured before and after treatment. The correlation between platelet count, platelet distribution width (PDW), mean platelet volume (MPV), and growth factor concentrations in the PRP group and clinical efficacy as well as pathway biomarker changes was analyzed. Results: VAS and WOMAC scores were lower in the PRP group at all time points (P<0.05). At 6 months, synovial IL-1β, TNF-α, IL-6, and p-p65 levels were significantly reduced from baseline in both groups (P<0.05), while the expression levels of IκBα were significantly increased (P<0.05). Moreover, the improvement in these parameters was significantly greater in the PRP group compared to the HA group, with statistically significant differences (P<0.05). Pearson correlation analysis revealed that all quality parameters of PRP were significantly positively correlated with the WOMAC improvement rate (P<0.05). Platelet count (PLT) and TGF-β correlated negatively with ΔIL-1β (P<0.05) and significantly positively correlated with △IκBα (P<0.05), respectively. PLT, TGF-β, and VEGF were significantly negatively correlated with △p-p65 (P<0.05). Conclusion: PRP may exert anti-inflammatory and joint-protective effects by inhibiting the NF-κB pathway, demonstrating superior therapeutic efficacy compared to hyaluronic acid. Its therapeutic effects are influenced by PRP heterogeneity, providing theoretical basis and guidance for the standardized clinical application of PRP in the treatment of KOA.