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Abstract Liver fibrosis and cirrhosis have limited therapeutic options and represent a serious unmet patient need. Recent use of single‐cell RNA sequencing (scRNAseq) has identified enriched cell types infiltrating cirrhotic livers but without defining the microanatomical location of these lineages thoroughly. To assess whether fibrotic liver regions specifically harbor enriched cell types, we explored whether whole‐tissue spatial transcriptomics combined with scRNAseq and gene deconvolution analysis could be used to localize cell types in cirrhotic explants of patients with end‐stage liver disease (total n = 8; primary sclerosing cholangitis, n = 4; primary biliary cholangitis, n = 2, alcohol‐related liver disease, n = 2). Spatial transcriptomics clearly identified tissue areas of distinct gene expression that strongly correlated with the total area (Spearman r = 0.97, p = 0.0004) and precise location (parenchyma, 87.9% mean congruency; range, 73.1%–97.1%; fibrosis, 68.5% mean congruency; range, 41.0%–91.7%) of liver regions classified as parenchymal or fibrotic by conventional histology. Deconvolution and enumeration of parenchymal and fibrotic gene content as measured by spatial transcriptomics into distinct cell states revealed significantly higher frequencies of ACTA2+ FABP4+ and COL3A1+ mesenchymal cells, IL17RA+ S100A8+ and FCER1G+ tissue monocytes, VCAM1+ SDC3+ Kupffer cells, CCL4+ CCL5+ KLRB1+ and GZMA+ IL17RA+ T cells and HLA‐DR+, CD37+ CXCR4+ and IGHM+ IGHG+ B cells in fibrotic liver regions compared with parenchymal areas of cirrhotic explants. Conclusion: Our findings indicate that spatial transcriptomes of parenchymal and fibrotic liver regions express unique gene content within cirrhotic liver and demonstrate proof of concept that spatial transcriptomes combined with additional RNA sequencing methodologies can refine the localization of gene content and cell lineages in the search for antifibrotic targets.