Background: Myeloid-derived suppressor cells (MDSCs) drive immunosuppression in the hepatocellular carcinoma (HCC) tumor microenvironment (TME), contributing to immune checkpoint blockade (ICB) resistance. This review explores underlying mechanisms and therapeutic strategies. Methods: We synthesize the recent literature on MDSC biology in HCC, focusing on signaling pathways, metabolic/epigenetic reprogramming, and novel interventions, including AI-driven analyses. Results: Key mechanisms include JAK–STAT3 activation for MDSC expansion, CXCL12-CXCR4 for recruitment, enhanced glycolysis/lipid metabolism for suppressive function, and epigenetic changes sustaining immunosuppression. Therapeutic approaches encompass inhibitors, differentiation promoters, metabolic modulators, transcriptional reprogramming, microbiome modulation, and combinations with ICB/locoregional therapies or standard chemoimmunotherapy, yielding improved outcomes in trials. Conclusions: Targeting MDSC redundancies via multi-modal strategies offers a roadmap for overcoming resistance, with AI enhancing biomarker-guided precision immunotherapy in HCC.