The clinical impact of viral neuroinvasion on the central nervous system (CNS) ranges from barely detectable to deadly, including acute and chronic outcomes. Developing innovative therapeutic strategies is important to mitigate virus-induced neurological and psychiatric disorders. A key gatekeeper to the CNS is the neurovascular unit (NVU), a major obstacle to viral neuroinvasion and antiviral therapies. The NVU isolates the brain from the blood through firm sealing operated by the tight junctions (TJs) of endothelial cells. Here, we make the thought-provoking assumption that TJs can be targets to prevent or treat viral neuroinvasion and resulting disorders. This review aims at defining the conceptual diverse mode of actions of such approaches, evaluates their feasibility, and discusses future challenges in the field.