Hepatocellular carcinoma is the most common type of primary liver cancer, with high heterogeneity. The differential gene expression of tumor cells, abnormal distribution of cell subsets, and complex cell interactions in tumor microenvironment are crucial factors leading to the failure of immune and targeted therapies in some patients. Understanding the heterogeneity of hepatocellular carcinoma is of great importance when exploring the mechanism of drug resistance and developing new treatment strategies. Molecular expression profiles could be disclosed by spatiotemporal omics at the tissue and cellular levels across continuous time and space dimensions. Recently, spatial transcriptome and spatial proteomics, the representative of spatiotemporal omics technologies, have developed rapidly. They not only reveal the characteristics of tissue expression profiles while retaining spatial location information, but also uncover the distribution, localization and interaction of molecules in cells or tissues, providing a new perspective for analyzing the heterogeneity of tumor microenvironment and the difference of therapeutic responses in hepatocellular carcinoma. This article reviews the progress on spatiotemporal omics techniques in revealing the heterogeneity of hepatocellular carcinoma, including the heterogeneity of cell subsets, tumor microenvironment and therapeutic response.