The current study was assigned to investigate the effect of TSA in comparison to zebularine on mitochondrial/intrinsic pro-apoptotic (Bax, Bim, and Bak) and anti-apoptotic (Bcl-2, Mcl-1, and Bcl-xL) genes and cytoplasmic/extrinsic (DR4, DR5, FAS, FAS-L, and TRAIL genes) pathways, DNA methyltransferase 1, 3a, and 3b, histone deacetylase inhibitors 1, 2, and 3, cell viability, and apoptosis in hepatocellular carcinoma SK-Hep 1, human colorectal cancer SW620, and human pancreatic cancer PaCa-44 cell lines. Here, DNMT1 is linked to colorectal cancer.