Despite the exciting progress that has been made in investigating natural products as modulators of colon cancer therapy in various studies and the broad benefits in miRNA regulation, such as the classical downregulation of cancer cell-associated miRs (e.g., miR-21, the miR-17-92 cluster, and miR-92) enabling tumor suppressor genes (p53, PDCD4, and PTEN), the potential to modulate treatment-resistant cells, and the use of natural products to treat colon cancer through epigenetics, numerous issues remain to be addressed. This evidence concerns the gene TP53 and cancer.