Obesity is closely associated with non-alcoholic fatty liver disease which will develop into hepatocellular carcinoma (HCC). Obesity per se is also an independent risk factor for HCC. Lipotoxicity, adipose tissue remodeling, modulation of immune infiltrates in tumors and adipocytes, changes in intestinal microbiome all contribute to the pathogenesis of HCC under obesity condition. These obesity-associated pathogenic factors increase the clinical challenges for the management of obesity-driven HCC. Scutellaria baicalensis Georgi is a perennial herb of the Lamiaceae family. It is clinically used for the treatment of hyperlipemia, atherosclerosis, hypertension and inflammatory diseases. This article reviews the current findings on the molecular basis of the anti-HCC effects of S. baicalensis and its bioactive compounds, and discuss whether the treatments can alleviate or ameliorate the obesity-associated pathogenic factors. This is the first review unravels the therapeutic potential of S. baicalensis and its bioactive compounds for the treatment obesity-driven HCC.