Objective: This study aims to investigate the impact of a combined intervention of intra-articular injections of platelet-rich plasma (PRP) and sodium hyaluronate, followed by traditional Chinese medicine (TCM) hot compress therapy, on serum levels of interleukin-1β (IL-1β) and interleukin-6 (IL-6) in patients with knee osteoarthritis (KOA). Additionally, it seeks to assess the clinical effectiveness and elucidate the potential mechanisms of this integrated treatment approach. Methods: A total of 86 KOA patients admitted to our hospital between August 2024 and July 2025 were randomly assigned to a study group and a control group, each with 43 patients. The control group was treated with intra-articular injection of PRP combined with sodium hyaluronate, while the study group received additional application of a TCM hot compress pack. Clinical efficacy, pain intensity (assessed using the numerical rating scale, NRS), joint function (evaluated using the WOMAC index), serum levels of IL-1β and IL-6, and quality of life (measured using the SF-36 scale) were compared between the two groups before and after the intervention. Results: The study group demonstrated a significantly greater total effective rate compared to the control group (P < 0.05). Following treatment, the study group exhibited markedly reduced NRS and WOMAC scores, along with lower serum levels of IL-1β and IL-6, all significantly superior to the control group (P < 0.05). Conversely, SF-36 scores in the study group were significantly elevated compared to the control group (P < 0.05). Conclusion: Intra-articular injection of PRP combined with sodium hyaluronate, supplemented by TCM hot compress pack, can effectively regulate serum IL-1β and IL-6 levels in KOA patients, alleviate pain, improve joint function and quality of life, and has good clinical application value.