Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element‐binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78‐kDa cell‐surface glycoprotein or SREBP cleavage‐activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine‐induced HCC progression by down‐regulating tumor‐promoting cytokines, including interleukin (IL)‐6, tumor necrosis factor alpha, and IL‐1β. Conclusion: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936‐1947).