It remains unclear whether activated inflammatory macrophages can adopt features of tissue-resident macrophages, or what mechanisms might mediate such a phenotypic conversion. Here we show that vitamin A is required for the phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80^intCD206⁺PD-L2⁺MHCII⁺ macrophages into macrophages with a tissue-resident F4/80^hiCD206⁻PD-L2⁻MHCII⁻UCP1⁺ phenotype in the peritoneal cavity of mice and during the formation of liver granulomas in mice infected with Schistosoma mansoni. The phenotypic conversion of F4/80^intCD206⁺ macrophages into F4/80^hiCD206⁻ macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A–deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, which indicates that failure to convert macrophages from the F4/80^intCD206⁺ phenotype to F4/80^hiCD206⁻ may lead to dysregulated inflammation during helminth infection.