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Summary Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3′ Igh super-enhancer, 3′ regulatory region (3′RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3′RR. In B cells, ZMYND8 binds promoters and super-enhancers, including the Igh enhancers. ZMYND8 controls the 3′RR activity by modulating the enhancer transcriptional status. In its absence, there is increased 3′RR polymerase loading and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh, which is also dependent on the 3′RR. Thus, ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3′ Igh super-enhancer., Graphical Abstract, Highlights • ZMYND8 is required for GLT of acceptor S regions and Class Switch Recombination • ZMYND8 supports efficient somatic hypermutation of the Igh variable regions • ZMYND8 binds B cell super-enhancers, including the 3′ Igh enhancer • ZMYND8 modulates the transcriptional status and activity of the 3′ Igh enhancer, Antibody diversity is essential for the establishment of an effective immune response. Delgado-Benito and Rosen et al. report that diversification of the immunoglobulin heavy chain (Igh) gene in mature B lymphocytes is regulated by the chromatin reader ZMYND8, which binds to and modulates the activity of the 3′ Igh locus super-enhancer.