Trained Immunity describes the capacity of innate immune cells to develop non-specific memory in response to certain exogenous exposures via metabolic and epigenetic reprogramming. This phenomenon mediates the heterologous beneficial effects of the BCG vaccine. Using an ex vivo model of trained immunity, we show that direct BCG exposure induces a persistent epigenetic and transcriptional signature in human monocytes, specifically training genes involved in interferon and viral pathways. By performing DNA methylation profiling of neonates from the MIS-BAIR clinical trial, we identify a BCG-associated DNA methylation signature in circulating monocytes >1 year after vaccination using. Genes associated with this epigenetic signature are involved in viral response pathways and are responsive to BCG exposure in mouse hematopoietic stem cells. The viral response signature after BCG vaccination is in line with the reported heterologous protection against viral infections reported in neonates, adults, and the elderly. Our findings indicate that the reported non-specific effects of BCG are accompanied by epigenetic remodelling of circulating monocytes that last as long.