Objective: To explore the effect of external application of Daxusong plaster combined with acupuncture therapy in treating knee osteoarthritis and the impact on serum indexes and pain. Methods: According to the treatment plan, 120 patients with knee osteoarthritis were divided into the acupuncture group (conventional acupuncture) and the treatment group (acupuncture combined with external application of Daxusong plaster), with 60 cases in each group. The efficacy, TCM syndrome scores, serum indexes [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cartilage oligomeric matrix protein (COMP), C-terminal cross-linked telopeptide of type II collagen (CTX-II), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG)], pain degree [Visual Analog Scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)], and adverse reactions were compared between the two groups. Results: After treatment, the total effective rate and OPG level in the treatment group were higher than those in the acupuncture group (P<0.05), while TCM syndrome scores, VAS scores, WOMAC, IL-6, TNF-α, COMP, CTX-II, and RANKL were lower than those in the acupuncture group (P<0.05). There was no statistically significant difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion: External application of Daxusong plaster combined with acupuncture is effective in treating KOA (cold-dampness obstruction syndrome), which can effectively alleviate clinical symptoms and pain, improve inflammation and bone metabolism, and has good safety.