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Abstract Hepatocytes are a major parenchymal cell type in the liver and play an essential role in liver function. Hepatocyte-like cells can be differentiated in vitro from induced pluripotent stem cells (iPSCs) via definitive endoderm (DE)-like cells and hepatoblast-like cells. Here, we explored the in vitro differentiation time-course of hepatocyte-like cells. We performed methylome and transcriptome analyses for hepatocyte-like cell differentiation. We also analyzed DE-like cell differentiation by methylome, transcriptome, chromatin accessibility, and GATA6 binding profiles, using finer time-course samples. In this manuscript, we provide a detailed description of the dataset and the technical validations. Our data may be valuable for the analysis of the molecular mechanisms underlying hepatocyte and DE differentiations.