<p>Hepatocellular carcinoma (HCC) remains a major global cause of cancer-related deaths. HCC development, immune evasion, and treatment resistance are significantly influenced by the aberrant activation of the NF-κB and JAK/STAT signaling pathways. The review provides a thorough and critical analysis of recent developments in nanocarrier-mediated targeting of NF-κB and JAK/STAT pathways in HCC. It demonstrates the molecular interactions between various pathways and their implications for inflammation, angiogenesis, hepatocarcinogenesis, and resistance to both immunotherapy and chemotherapy. A variety of nanoplatforms, such as polymeric nanoparticles, lipid-based systems, inorganic nanomaterials, and biomimetic carriers, are designed to enhance the delivery of small-molecule inhibitors, nucleic acids, and combination therapies, improving pharmacokinetic and pharmacodynamic profiles. The review highlights ligand-functionalized and stimulus-responsive nanocarriers designed for controlled drug release and targeted therapy in the liver environment. Co-modulation of NF-κB and JAK/STAT signaling via nanotechnology enhances antitumor efficacy and decreases systemic toxicity, as supported by preclinical and recent translational data. Lastly, important issues such as scalability, biosafety, and regulatory concerns are discussed. Future directions for integrating precision cancer techniques with nanomedicine are proposed. This analysis emphasizes the therapeutic potential of targeting the NF-κB and JAK/STAT pathways with nanotechnology to enhance outcomes in HCC.</p> Graphical Abstract <p></p>