Inflammation is a cardinal feature of viral infections of the central nervous system (CNS) and is defined by activation of both innate and adaptive immune processes that not only exert antiviral actions, but also mediate pathogenic off‐target effects. Indeed, systemic inflammation often exacerbates local inflammation within the CNS during viral infections, in part by enhancing the trafficking of virus‐infected (and ‐activated) cells across the blood–brain barrier. Human immunodeficiency virus (HIV) type CNS entry and infection of microglia and macrophages occurs soon after primary infection and establishes a long‐lasting viral reservoir. Innate immune activation during HIV‐1 infection is characterized by type 1 interferon‐related gene expression as well as proinflammatory cytokines, proteases, and reactive oxygen species (ROS) that contribute to synaptic injury and eventual neuronal death. This chronic innate immune activation results in a low‐grade encephalitis and the eventual development of the clinical spectrum disorder, HIV‐associated neurological disorder (HAND), years after primary infection. In contrast, West Nile virus (WNV) causes a rapid onset of encephalitis, meningitis, and myelitis, which is characterized by infection of neurons with associated lymphocyte and macrophage CNS infiltration that underlie acute innate and adaptive immune responses leading to tissue damage. Herein, we compare inflammatory aspects of these viral infections of the CNS, highlighting the associated pathogenic and protective mechanisms.