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The objective of the study is to determine adipokine-associated mechanism of efficacy of Si He Decoction (SHD) for treating non-alcoholic fatty liver disease (NAFLD). Forty-five Sprague-Dawley (SD) rats were randomly divided into control group, model group, SHD low-dose group, SHD middle-dose group, and SHD high-dose group. Except control group, others were fed with a high-fat diet for 12 weeks to establish model. Then, H&E and oil red O staining were performed, and enzyme-linked immunosorbent assay (ELISA) was used to detect expression level of adipokine-associated molecules. H&E and oil red O staining results revealed that SHD treatment for NAFLD could effectively improve liver pathological conditions compared to that in model group, and the best efficacy was observed in SHD high-dose group. Compared to model group, SHD treatment could effectively downregulate expression level of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and upregulate expression level of visfatin, adiponectin (APN), leptin (LEP), and resistin in NAFLD rats. SHD can improve NAFLD through multiple means of targeting adipokines.