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Pathogenic herpesviruses including cytomegalovirus target numerous host organs during infection, but the immunological mechanisms that afford antiviral protection in different tissue microenvironments require a better understanding. Utilizing the murine cytomegalovirus (MCMV) model, we demonstrate that neutrophils are critical antiviral effector cells that counter acute herpesvirus infection. Depletion of Ly6G+ neutrophils exacerbated virus-induced weight loss and elevated virus load in a tissue-restricted manner. Neutrophils profoundly and directly inhibited virus replication in vitro. MCMV-elicited neutrophil responses were orchestrated by interleukin-22 (IL-22), which was expressed by conventional NK cells and induced neutrophil-attractant chemokines in MCMV-infected peripheral organs. These data demonstrate that IL-22 affords anti-herpesvirus infection in peripheral tissue and highlights a previously unappreciated and critical role for neutrophils in countering cytomegalovirus infection.