West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infection is largely controlled by the immune response in the periphery but in some cases WNV bypasses this response and invades the central nervous system (CNS), causing encephalitis and encephalomyelitis. Recent studies indicate that DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) and its downstream adaptor molecule STimulator of INterferon Gene (STING) are required for host defense against neurotropic RNA viruses; however the mechanism of the cGAS-STING pathway on viral control is unknown. For this study, we evaluated the role of cGAS-STING signaling in host defense through virologic control and immune defense against WNV in the CNS using a murine model of infection. When infected with WNV, both cGAS and STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. STING-/- mice exhibited increased and prolonged neurological symptoms compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, particularly in survivors. To determine if innate immune actions against WNV required cGAS-STING signaling, we infected primary bone-marrow derived macrophages (BMDM) and determined the virologic and immunologic response. We found that cGAS-STING signaling was neither required for innate immune activation nor control of WNV replication in BMDM. In contrast, in vivo analyses revealed that cGAS-/- and STING-/- mice have defective CD8 T cell responses that associate with increased CNS viral load pathology from WNV infection. Our findings demonstrate that cGAS-STING signaling plays an important role in CNS immune control against WNV infection, and reveal immune mechanisms of control against neuroinvasive virus infection.