Herpes simplex viral infections, including herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), are exceptionally common worldwide. These viruses establish lifelong persistent infections with cycles of lytic reactivation to produce recurrent diseases including oral and genital lesions, herpetic keratitis/blindness, congenital-developmental syndromes, and viral encephalitis. Infection with HSV-2 increases the rate of human immunodeficiency virus (HIV) transmission in coinfected individuals. DNA replication inhibitors are typically used to treat herpesvirus infections. However, these compounds do not completely suppress infection, viral shedding, reactivation from latency, and the inflammation that contributes to diseases such as keratitis. An unmet need continues to exist for methods of preventing or treating herpesviral infections. The application claims methods of preventing or treating herpesviral infection of a host, comprising administering to the host an effective amount of an inhibitor of the EZH1/2 histone methyltransferase activities. The application is not limited to herpes simplex virus but rather is applicable to other viral infections as well.