Plasma cells (PCs) play a major role in the defense of the host organism against pathogens. We have shown that PC generation can be modeled using multi-step culture systems that reproduce the sequential cell differentiation occurring in vivo. Using this unique model, we investigated the role of EZH2 during PC differentiation (PCD) using H3K27me3 and EZH2 ChIP-binding profiles. We then studied the effect of the inhibition of EZH2 enzymatic activity to understand how EZH2 regulates the key functions involved in PCD. EZH2 expression significantly increases in preplasmablasts with H3K27me3 mediated repression of genes involved in B cell and plasma cell identity. EZH2 was also found to be recruited to H3K27me3-free promoters of transcriptionally active genes known to regulate cell proliferation. Inhibition the catalytic activity of EZH2 resulted in B to PC transcriptional changes associated with PC maturation induction, as well as higher immunoglobulin secretion. Altogether, our data suggest that EZH2 is involved in the maintenance of preplasmablast transitory immature proliferative state that supports their amplification.