Alterations in RNA splicing are associated with cancer, but it is not clear whether they result from malignant transformation or have a causative role. We show here that hepatocyte‐specific deletion of serine/arginine‐rich splicing factor 3 (SRSF3) impairs hepatocyte maturation and metabolism in early adult life, and mice develop spontaneous hepatocellular carcinoma (HCC) with aging. Tumor development is preceded by chronic liver disease with progressive steatosis and fibrosis. SRSF3 protects mice against CCl₄‐induced fibrosis and carcinogenesis and suppresses inclusion of the profibrogenic EDA exon in fibronectin 1. Loss of SRSF3 increases expression of insulin‐like growth factor 2 and the A‐isoform of the insulin receptor, allowing aberrant activation of mitogenic signaling, promotes aberrant splicing and expression of epithelial to mesenchymal transition (EMT) genes, and activates Wnt/β‐catenin signaling leading to c‐Myc induction. Finally, SRSF3 expression is either decreased or the protein mislocalized in human HCC. Conclusion: Our data suggest a potential role for SRSF3 in preventing hepatic carcinogenesis by regulating splicing to suppress fibrosis, mitogenic splicing, and EMT. Thus, these mice may provide an attractive model to discover the pathogenic mechanisms linking aberrant pre–messenger RNA splicing with liver damage, fibrosis, and HCC. (Hepatology 2015;61:171–183)