Nucleoside analogue-based drugs control herpes simplex virus type 1 (HSV-1) infection of the eye, but are limited by potential drug resistance and adverse effects. Jaishankar and colleagues report that the small-molecule TANK-binding kinase 1 (TBK1) inhibitor, BX795, suppresses HSV-1 infection in transformed and primary human cells, organ cultures of human and pig corneas, and in a mouse model of ocular HSV infection. This antiviral activity was mediated by an off-target effect, comprised of inhibition of AKT phosphorylation in infected cells, leading to blockade of viral protein synthesis.