Humans display remarkable inter-individual variation in immune response, in part due to population specific adaptations resulting from different pathogenic environments encountered during the out of Africa movement. To date, most of the variance in transcriptional differences in immune responses remains unaccounted for when considering genetics alone, suggesting other mechanisms at play. Epigenetics is known to play a central role in the regulation of immune response, yet few studies have investigated how genetic ancestry and genetic variation impact epigenetic signatures in response to pathogens. To investigate this, we carried out in-depth genetic, epigenetic, and transcriptional profiling on primary macrophages derived from a panel of individuals with varying proportions of European and African ancestry before and after infection with influenza A virus (IAV). We find that the immune response to IAV infection involves a coordinated response of the gene regulatory landscape, and that both transcriptional and epigenetic effects act to upregulate main inflammatory response pathways. Baseline epigenetic profiles are strongly predictive of the transcriptional response to IAV across individuals, and ancestry-associated differences in gene expression are tightly coupled with variation in enhancer activity. Quantitative trait locus (QTL) mapping reveals highly coordinated genetic effects on gene regulation with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. We find epigenetic ancestry-associated differences are genetically controlled, even more so than gene expression, and that epigenetic QTL are also more frequently associated with immune-disease risk. Lastly, we explore inter-individual and intra-individual variability in DNA methylation levels and corresponding transcriptional response in DNA methylation-dependent enhancer regions, revealing that baseline DNA methylation predicts transcriptional response. Together, our results provide a comprehensive characterization of the genetic and epigenetic basis of variation in immune response to IAV infection in individuals of European and African ancestry.