The tumor microenvironment (TME) is influenced by a "disorganized" extracellular matrix (ECM) that sensitizes cancer cells toward mechanical stress, signaling, and structural alterations. In hepatocellular carcinoma (HCC), lack of knowledge about key ECM proteins driving the TME refractory to targeted therapies poses a barrier to the identification of new therapeutic targets. Herein, we discuss the contributions of various ECM components that impact hepatocytes and their surrounding support network during tumorigenesis. In addition, the underpinnings by which ECM proteins transduce mechanical signals to the liver TME are detailed. Finally, in view of the bidirectional feedback between the ECM, transformed hepatocytes, and immune cells, we highlight the potential role of the ECM disorganization process in shaping responses to immune checkpoint inhibitors and targeted therapies. Our comprehensive characterization of these ECM components may provide a roadmap for innovative therapeutic approaches to restrain HCC.