Abstract The live-attenuated Bacille Calmette-Guérin (BCG) vaccine has been introduced a century ago to prevent tuberculosis and is still administered to >80% of newborns worldwide. Independent of its effect on TB, BCG introduction markedly reduced childhood mortality. Although BCG vaccine is routinely administered to infants, there is a gap in understanding the influence of BCG on the neonatal immune system. In adults, BCG induces trained or heterologous immunity. Here, to better understand the molecular changes in the infant immune system after BCG immunization, we performed RNA sequencing and ATAC sequencing in circulating CD4 T cells and monocytes of 28 infants prior to and 6–12 weeks after administering BCG. Consistent with data from BCG-vaccinated adults, the expression profile of 168 differentially expressed genes (DEG) supports the activation of monocytes after BCG vaccination, and ATAC sequencing data identified epigenetic modification that impact accessibility of genes in Nod1 and Nod 2 signaling pathways. In CD4 T cells, we identified a total of 322 DEG, including 95 upregulated and 226 downregulated genes. The functional enrichment and transcription factor analysis showed the enrichment of ErbB signaling pathways which regulate cell proliferation and differentiation mediated through MAPK signaling pathways. These results combined with peaks identified by ATAC sequencing were indicative of the expansion of Th1 CD4 T cells in BCG vaccinated infants. This study provides an understanding of molecular changes in monocytes and CD4 T cells after BCG vaccination that may explain the improved capacity of the infant immune system to respond to intracellular pathogens.