As per our knowledge, our study is the first to decipher the role of piperine in mitigating experimental colon cancer in Wistar rats by regulating cross-talk between the Nuclear factor kappa light chain enhancer of activated B cells (NF-kB-p65) and Nuclear factor erythroid 2-related factor 2 (Nrf-2) pathway to discover novel targets for the prevention of chemically induced-colon cancer which simulates human colon cancer pathology. This evidence concerns the gene NFE2L2 and colonic neoplasm.