Objective To explore synergistic clinical effect of the combination of Qufeng Huoluo pills and Zhixiang tablets for treatment of osteoarthritis. Methods 160 patients diagnosed with osteoarthritis and treated in our hospital from October 2017 to May 2019 were randomly divided into four groups, and were treated with Qufeng Huoluo Pills, Zhixiang Tablets, Qufeng Huoluo Pills/Zhixiang Tablets and Glucosamine Sulfate Capsules, respectively. After 3 months’ of treatment, the clinical efficacy and adverse reactions were evaluated and statistically analyzed by Xray plain film signs, magnetic resonance images, Western Ontario McMaster index and Lequesne pain and function index.Results Compared with the singledrug group, the Xray films signs of the combination group of Qifeng Huoluo Pills/ Zhixiang Tablets showed narrower joint space and obvious reduction of callus with decreased KL grade. MRI results showed that joint capsule fluid, edema and cartilage defect were significantly alleviated with reduced Recht grade. The WOMAC osteoarthritis index (P＜0.05) and the Lequesne pain and function index were significantly lower (P＜0.01). The q(1.25) demonstrated that the combined administration had a synergistic effect. At the same time, compared with glucosamine sulfate, the combination group has comparable efficacy while fewer adverse reactions. Conclusion The clinical efficacy of Qifeng Huoluo pill/ Zhixiang tablets in treatment of osteoarthritis is better than that of single administration. It has synergistic effect and is equivalent to the effect of glucosamine sulfate with fewer side effects.