Non-alcoholic steatohepatitis (NASH) has become a global health issue, which poses additional financial burden to public health care. However, no specific pharmacological therapy is recommended in current guidelines. Ursolic acid (UA) has been proven to perform multiple biological activities, thereby having a broad application prospect in healthcare field. Thus, this current research was conducted to investigate the protective mechanisms of UA on NASH. Integrative genomic analyses were performed to identify characteristic genes for NASH, and human proteomics chip was applied to seek out differentially binding proteins for UA. The combining bioinformatic analyses revealed 529 and 502 differentially expressed genes for NASH and UA, respectively. And further enrichment analyses indicated that IGF-IR signaling pathway was intimately involved in the therapeutic effects of UA on NASH. Experimental studies displayed that UA up-regulated the decorin expression to activate IGF-IR signaling as well as to inhibit HIF-1 signaling, resulting in alleviation on metabolic dysfunction, liver steatosis, inflammation and hypoxia in high-fat-fed mice. And additionally, these results were confirmed by lipotoxic and decorin-interference cell model. Taken together, we found that UA could regulate IGF-IR and HIF-1 signaling pathways via decorin to provide dual protective functions on metabolic dysfunction and liver hypoxia, and therefore turned to be an effective option for the treatment of NASH.