Approximately 8-10% of the global population is affected by autoimmune diseases (ADs), which encompass a wide array of idiopathic conditions resulting from dysregulated immune responses. The enzymatic component of the polycomb-repressive complex 2 (PRC2), enhancer of zeste homolog 2 (EZH2, also referred to as KMT6), functions as a methyltransferase possessing a SET domain that plays crucial roles in epigenetic regulation, explicitly facilitating the methylation of histone H3 at lysine 27. Notably, EZH2 is catalytically inactive and requires association with EED and SUZ12 to form an active PRC2 complex. Hyperactivation of EZH2 has been implicated in various malignancies, prompting the development of EZH2 inhibitors as therapeutic agents for several cancers, including lymphoma, prostate, breast, and colon cancer. The application of EZH2-targeting therapies has also been explored in the context of autoimmune diseases. While there have been advancements in certain ADs, responses can vary significantly, as evidenced by mixed outcomes in cases such as inflammatory bowel disease. Consequently, the dual role of EZH2 and the therapeutic potential of its inhibitors in the treatment of ADs remain nascent fields of study. This review will elucidate the interplay between EZH2 and autoimmune diseases, highlighting emerging insights and therapeutic avenues.