Abstract: OBJECTIVE  To discuss the effect of Zhihuang Zhitong Powder on acute ankle sprain and morphology of injured ligament.METHODS  The 92 patients with acute ankle sprain were randomly divided into the control group and the observation group, 46 cases each. The control group was given the basic therapy combined with Diclofenac Diethylamine Emulgel while the observation group was given the basic therapy combined with Zhihuang Zhitong Powder. The course lasted 14 days. The efficacy of the two groups were compared after treatment in terms of those indexes, including the pain score of visual analogue scale (VAS), the level of serum oxidative stress factors, the ankle circumcision, the ankle flexion, the activity of back extension, the thickness of damaged ligament and the changes in ankle function. The period of pain relief and swollen joint recovery along with adverse skin reactions in the two groups were recorded.RESULTS  After treatment, the pain score of VAS, the thickness of the anterior cruciate ligament and the anterior cruciate ligament, the ankle circumcision, scores of the ankle flexion, the activity of back extension, as well as the ankle and hind foot function evaluation table were significantly improved(P < 0.05). The activity of superoxide dismutase (SOD) was higher than before treatment (P < 0.05). The level of alondialdehyde (MDA), fibroblast growth factor (FGF)-2, conversion growth factor (TGF)-β1, matrix metalloproteinases (MMP)-9 and interleukin-1β (IL-1β) were lower than those of the same group before treatment. the observation group was higher than that in the control group (P < 0.05). The total efficiency of the observation group was better than that of the control group (P < 0.05). The period of pain relief and swollen joint recovery in the observation group were shorter than those of the control group (P < 0.05). There was no statistical difference in the incidence of adverse skin reactions in the two groups (P>0.05).CONCLUSION  The effect of Zhihuang Zhitong Powder in the treatment of acute ankle sprain was better than that of Diclofenac Diethylamine Emulgel, which can enhance antioxidant activity, inhibit oxidative stress response, improve lateral ligament morphology, and promote the recovery of ankle function.