In summary, our data indicate that the synergistic effects of PRIMA‐1met and L‐OHP on CRC cells through both p53‐dependent and ‐independent modalities, such as intrinsic and extrinsic apoptotic pathways, cell cycle arrest, and relevant stress response characterized by alterations in redox balance, metabolic processes, and ER functionality. This evidence concerns the gene TP53 and colorectal carcinoma.