Hepatocellular carcinoma (HCC) causes significant morbidity and high fatal outcome globally. Conventional therapeutic strategies for HCC have achieved significant improvements, but they have limitations and are far from ideal. Novel nanoparticulate drug delivery systems have recently presented great therapeutic potential for cancer therapeutics. Appropriate and accurate animal models (main mice) are the basis of preclinical and translational research of nanoparticulate drug formulations in HCC. This review will provide an overview of different animal models of HCC, with a particular emphasis on those applied to assess the clinical potential for drug nanopharmaceutics.