Abstract: [Objective] To explore the efficacy and possible mechanism of arthroscopic debridement combined with platelet rich plasma (PRP) in the treatment of moderate to severe knee osteoarthritis (KOA). [Methods] A total of 90 patients with moderate to severe KOA admitted to XX Hospital from January 2021 to March 2022 were randomly divided into a combination group and a control group, with 45 cases per group receiving arthroscopic debridement combined with PRP treatment, and arthroscopic debridement only. The perioperative conditions, laboratory indicators, and follow-up data were compared between the two groups. [Results] There was no significant difference in perioperative related indicators such as surgical time and postoperative complications between the two groups (P>0.05). After treatment, the levels of serum Toll-like receptor-4 (TLR-4), matrix metalloproteinase-9 (MMP-9), and stromal cell derived factor-1 (SDF-1) in the combination group were significantly lower than those in the control group (P<0.05). The visual analog pain score (VAS), McMaster University Osteoarthritis Index (WOMAC), and Lysholm knee joint score in the combined group were significantly lower than those in the control group at 3 and 12 months after surgery (P<0.05), and the Lysholm knee joint score was significantly higher than that in the control group (P<0.05); The recurrence rate at 12 months after surgery in the combined group was lower than that in the control group, but there was no significant difference between the groups (P>0.05). [Conclusion] Arthroscopic debridement combined with PRP treatment may reduce the levels of TLR-4, MMP-9, and SDF-1 to alleviate pain and improve knee function in patients with moderate to severe KOA.