Enhancer of zeste homolog 2 (EZH2) serves a pivotal role in epigenetic silencing by acting as a histone methyltransferase. It has been confirmed that EZH2 overexpression occurs in different types of cancer and is involved in drug resistance, while it remains unclear how a DNA‑damaging event may promote EZH2 expression in multiple myeloma (MM) cells and how EZH2 influences its susceptibility to death in response to DNA‑damaging chemotherapy. The present study examined the impact of EZH2 inhibition on DNA damage‑induced apoptosis in MM cells and elucidated its underlying molecular mechanism. It was demonstrated that pharmacological inhibition of EZH2 sensitized MM cells to DNA‑damaging agents and promoted limited caspase‑dependent apoptosis. Mechanistically, targeting EZH2 with minimal toxic concentrations of a pharmacological inhibitor (GSK126) markedly weakened the accompanying increase in the histone trimethylation H3K27me3 and aggravated DNA damage response (DDR)‑associated apoptosis in vitro. These data preliminarily confirmed the underlying molecular mechanisms of interaction between histone methylation and the DDR in MM cells, forming the rationale for the combination regimen of EZH2 inhibitors with DNA‑damaging agents for the treatment of MM.