Tumor‐associated TP53 inactivation correlates with lipid droplet (LD) accumulation. High‐fat diets drive Cyb5r3‐Myh9‐mediated p53 enrichment on LD surfaces, accelerating its degradation while upregulating LD‐promoting factor CD36 expression to establish a feed‐forward loop. LD suppression or dietary intervention restores p53 and inhibits tumorigenesis, unveiling LD‐driven p53 regulation mechanisms and novel lipid‐metabolism‐targeted therapeutic strategies. Here, TP53 is linked to neoplasm.