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Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we used a systems biology approach to map the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza resulted in persistently reduced H3K27ac in monocytes and myeloid dendritic cells, which was associated with impaired cytokine responses to TLR stimulation. Single cell ATAC-seq analysis of 120,305 single cells revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were also observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at loci targeted by interferon response factors (IRFs). This was associated with elevated expression of antiviral genes and type 1 IFN production and heightened resistance to infection with the heterologous viruses Zika and Dengue. These results demonstrate that influenza vaccines stimulate persistent epigenomic remodeling of the innate immune system. Notably, AS03-adjuvanted vaccination remodeled the epigenome of myeloid cells to confer heightened resistance against heterologous viruses, revealing its potentially unappreciated role as an epigenetic adjuvant.