2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dose-dependently induces the development of hepatic fat accumulation and inflammation with fibrosis in mice. To investigate cell-specific and spatially resolved dose-dependent changes in gene expression elicited by TCDD, single-nuclei RNA sequencing (snRNAseq) was performed on frozen livers of male mice gavaged with sesame oil vehicle control or increased doses of TCDD (0.01, 0.03, 0.1, 0.3, 1, 3, 10, or 30 µg/kg) every 4 days for 28 days. The proportion of 11 cell (sub)types across 131,613 nuclei dose-dependently changed with 68% of all portal and central hepatocyte nuclei in control mice being overtaken by macrophages following TCDD treatment. We identified 368 (portal fibroblasts) to 1,339 (macrophages) differentially expressed genes. This work serves as valuable resource for the development of tools and analyses for large-scale in vivo dose-response experiments.