Abstract Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies. Here we use a multiparameter approach involving CD27 to segregate naïve B cells (NBCs), IgD+ unswitched (unsw) MBCs and IgG+ or IgA+ class-switched (sw) MBCs from humans of different age, sex and race. Conserved antibody variable gene expression indicates that MBCs emerge through unbiased selection from NBCs. Integrative analyses of mRNAs, miRNAs, lncRNAs, chromatin accessibility and cis-regulatory elements uncover a core mRNA-ncRNA transcriptional signature shared by IgG+ and IgA+ swMBCs and distinct from NBCs, while unswMBCs display a transitional transcriptome. Some swMBC transcriptional signature loci are accessible but not expressed in NBCs. Profiling miRNAs reveals downregulated MIR181 and concomitantly upregulated target-genes RASSF6, TOX, TRERF1, TRPV3 and RORa in swMBCs. Finally, lncRNAs differentially expressed in swMBCs cluster proximal to chromosome 14 IgH chain locus. Our findings provide new insights into MBC transcriptional programs and epigenetic regulation, opening new investigative avenues on these critical cell elements in human health and disease.