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Context Wogonoside has many pharmacological activities, but whether it has a protective effect against non-alcoholic fatty liver disease (NAFLD) has not been reported. Objective This study investigates the protective effect of wogonoside against NAFLD in mice and its potential mechanism. Materials and methods C57BL/6 mice were randomly divided into control group, NAFLD group and low-, medium- and high-dose wogonoside groups (5, 10 and 20 mg/kg, respectively) (n= 12). Mice in the control group were fed with the standard diet, and those in NAFLD group and low-, medium- and high-dose wogonoside groups were fed with a high-fat diet. The different doses of wogonoside were administered by gavage once a day for 12 weeks. Results Compared with those in NAFLD group, the liver mass, liver index and the LDL, TG, TC, IL-2, IL-6, TNF-α, MDA and NF-κB p65 levels were decreased, and the SOD and GSH-Px activities, and HDL, IκBα, Nrf2 and HO-1 contents were increased in wogonoside groups. Compared with those in the NAFLD group, wogonoside (5, 10 and 20 mg/kg) reduced AST (132.21 ± 14.62, 115.70 ± 11.32 and 77.94 ± 8.86 vs. 202.35 ± 19.58 U/L) and ALT (104.37 ± 11.92, 97.53 ± 10.12 and 56.74 ± 6.33 vs. 154.66 ± 14.23 U/L) activities in the serum. Discussion and conclusions Wogonoside has a protective effect against NAFLD in mice, which may be related to its anti-inflammation and inhibition of oxidative stress, suggesting that wogonoside may be a potential therapeutic agent for the treatment of NAFLD.