Objective: To investigate the effect of diclofenac sodium combined with acupuncture on the score of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), quality of life and inflammatory factors in elderly patients with knee osteoarthritis (KOA). Methods: Ninety-four elderly patients with KOA were selected and divided into two groups through random number table method, 47 cases in each group. The control group was treated with diclofenac sodium, and the treatment group was further treated with acupuncture. The changes of pain, WOMAC score and quality of life were compared between the two groups before and after treatment, and the serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) were also compared. Results: After treatment, serum TNF-α, IL-6 levels in the two groups were decreased significantly, and the treatment group decreased more significantly (P<0.05); visual analogue scale (VAS) and WOMAC score in the two groups were significantly decreased, and the treatment group decreased more significantly (P<0.05); the scores of social function, psychological function, material life and physical function of generic quality of life inventory-74 (GQOL-74) in the two groups were significantly increased, and the treatment group increased more significantly (P<0.05). Conclusion: Diclofenac sodium combined with acupuncture in the treatment of elderly patients with KOA can reduce the level of serum inflammatory factors, significantly relieve pain symptoms and improve knee joint function, and improve the quality of life.