Mothers against decapentaplegic homolog 7 (SMAD7) is an antagonist of the transforming growth factor β (TGF-β) signaling. In the present investigation, we sought to determine the relevance of SMAD7 in liver carcinogenesis using in vitro and in vivo approaches. We found that SMAD7 is upregulated in a subset of human hepatocellular carcinoma (HCC) samples with poor prognosis. Gene set enrichment analysis (GSEA) revealed that SMAD7 expression correlates with activated YAP/NOTCH pathway and cholangiocellular signature genes in HCCs. These findings were substantiated in human HCC cell lines. In vivo, overexpression of Smad7 alone was unable to initiate HCC development, but it significantly accelerated c-Myc/MCL1 induced mouse HCC formation. Consistent with human HCC data, c-Myc/MCL1/Smad7 liver tumors exhibited an increased cholangiocellular gene expression along with Yap/Notch activation and epithelial-mesenchymal transition (EMT). Intriguingly, blocking of the Notch signaling did not affect c-Myc/MCL1/Smad7-induced hepatocarcinogenesis while preventing cholangiocellular signature expression and EMT, whereas ablation of Yap abolished c-Myc/MCL1/Smad7-driven HCC formation. In mice overexpressing a myristoylated/activated form of AKT, co-expression of SMAD7 accelerated carcinogenesis and switched the phenotype from HCC to intrahepatic cholangiocarcinoma (iCCA) lesions. In human iCCA, SMAD7 expression was robustly upregulated, especially in the most aggressive tumors and directly correlated with the levels of YAP/NOTCH targets as well as cholangiocellular and EMT markers. The present data indicate that SMAD7 contributes to liver carcinogenesis by activating the YAP/NOTCH signaling cascade and by inducing a cholangiocellular and EMT signature. This article is protected by copyright. All rights reserved.