The field of nanomedicine has provided a fresh approach to cancer treatment by addressing the limitations of current therapies and offering new perspectives on enhancing patients' prognoses and chances of survival. Chitosan (CS) is isolated from chitin that has been extensively utilized for surface modification and coating of nanocarriers to improve their biocompatibility, cytotoxicity against tumor cells, and stability. HCC is a prevalent kind of liver tumor that cannot be adequately treated with surgical resection in its advanced stages. Furthermore, the development of resistance to chemotherapy and radiotherapy has caused treatment failure. The targeted delivery of drugs and genes can be mediated by nanostructures in treatment of HCC. The current review focuses on the function of CS-based nanostructures in HCC therapy and discusses the newest advances of nanoparticle-mediated treatment of HCC. Nanostructures based on CS have the capacity to escalate the pharmacokinetic profile of both natural and synthetic drugs, thus improving the effectiveness of HCC therapy. Some experiments have displayed that CS nanoparticles can be deployed to co-deliver drugs to disrupt tumorigenesis in a synergistic way. Moreover, the cationic nature of CS makes it a favorable nanocarrier for delivery of genes and plasmids. The use of CS-based nanostructures can be harnessed for phototherapy. Additionally, the incur poration of ligands including arginylglycylaspartic acid (RGD) into CS can elevate the targeted delivery of drugs to HCC cells. Interestingly, smart CS-based nanostructures, including ROS- and pH-sensitive nanoparticles, have been designed to provide cargo release at the tumor site and enhance the potential for HCC suppression.