Hepatocellular carcinoma (HCC) is one of the therapeutically challenging liver cancer with high mortality rate in human worldwide. Animal model plays pivotal role in basic and translational research in cancer and which is most important for complex and challenging cancers such as hepatocellular carcinoma. Until now different animal models have been developed which includes induced, immunocompromised, humanized, genetically modified and syngeneic rodent models considering different etiological factors such as viral, chemical carcinogen, genetic mutation, alcoholism etc. Nowadays, orthotopic models of HCC which mimic similar microenvironment as like human HCC are commonly used and validation of these models are challenging, as characterization and quantification of the tumors is not easy due to anatomical and physiological peculiarities of liver. So non-invasive preclinical imaging techniques such as Computed Tomography (CT), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), Bioluminescence Imaging (BLI) and fluorescence Imaging are being utilized for better monitoring and understanding of tumor growth as well as to avoid mortality and to improve reproducibility of the data with minimum number of animals. This review provides an overview of recent developments in animal models for liver cancer research and also focusses on advances in validation of these models using non-invasive preclinical imaging modalities.