Thus, the present study was designed to investigate the antiproliferative activity of an Adiantum pedatum extract against chemically induced colon cancer in rats and address the implication of the mir-145/PI3K/AKT/c-MYC/PDCD-4—P53 signaling pathway in either the curative or prophylactic effect of the extract in comparison to a recently validated anticancer bioactive compound, piceatannol. Here, TP53 is linked to malignant colon neoplasm.