Cancer is one of the leading causes of morbidity and mortality worldwide. One of the primary causes of
cancer development and progression is epigenetic dysregulation, which is a heritable modification that
alters gene expression without changing the DNA sequence. Therefore, targeting these epigenetic
changes has emerged as a promising therapeutic strategy. Benzimidazole derivatives have gained
attention for their potent epigenetic modulatory effects as they interact with various epigenetic targets,
including DNA methyltransferases, histone deacetylases and histone methyltransferases. This review
provides a comprehensive overview of benzimidazole derivatives that inhibit different acetylation and
methylation reader, writer and eraser epigenetic targets. Herein, we emphasize the therapeutic potential
of these compounds in developing targeted, less toxic cancer therapies. Presently, some promising
benzimidazole derivatives have entered clinical trials and shown great advancements in the fields of
hematological and solid malignancy therapies. Accordingly, we highlight the recent advancements in
benzimidazole research as epigenetic agents that could pave the way for designing new multi-target
drugs to overcome resistance and improve clinical outcomes for cancer patients. This review can help
researchers in designing new anticancer benzimidazole derivatives with better properties.