Tumor cells evade immune surveillance by exploiting surface proteins that interact with immune checkpoint receptors, inhibiting immune cell activity. Immune checkpoint inhibitors (ICIs) counteract this by blocking these inhibitory signals, restoring the immune system's ability to target tumor cells. While ICIs show significant efficacy in cancer treatment, their clinical application is limited by low response rates and acquired resistance. In recent years, natural products have gained attention for their potential in modulating immune checkpoint expression and improving the tumor immune microenvironment, enhancing anti-tumor immune responses. Combining natural products with ICIs holds promise in overcoming resistance and improving therapeutic outcomes. This review summarized the molecular mechanisms of immune checkpoint regulation in tumor immune evasion, and emphasized the role of natural products in regulating tumor intrinsic factors (PD-L1 levels, immunogenic cell death, somatic mutations, chaperone-mediated autophagy and metabolic reprogramming), the immune microenvironment including CD8 (+) T cells, CD4(+) T cells, NK cells, Tregs, dendritic cells and MDSCs, and gut microbiota. We explored the potential of natural products in overcoming ICI resistance and enhancing anti-tumor immune responses and proposed combination strategies to optimize cancer immunotherapy.