Research efforts to establish therapeutic modalities for treating sickle cell disease (SCD) and β-thalassemia have been hindered by our incomplete understanding of the developmental regulation of human β-like globin gene expression. It has been demonstrated that increased embryonic globin (ε-globin) gene expression, similar to fetal globin (γ-globin), can ameliorate the severity of SCD and β-thalassemia in mice. Therefore, elucidating the molecular mechanism of ε-globin gene silencing is of biologic and clinical importance. Herein, we show that a histone lysine methyltransferase, SUV4-20h1, plays a critical role in silencing ε-globin gene expression in both K562 cells and primary erythroid progenitor cells. We found that ε-globin gene expression could be modulated by coordinate SUV4-20h1-dependent histone modification and DNA methylation. We also found that SUV4-20h1 repressed embryonic globin gene expression in mice, suggesting a conserved role for SUV4-20h1 during mammalian evolution. These results identify SUV4-20h1 as a novel epigenetic suppressor of ε-globin gene expression implying a potential alternative therapeutic approach for the treatment of β-thalassemia and SCD.