The Leptospira-associated acute encephalopathy syndrome (AES) is a severe neurological complication, largely affecting the endemic regions. Unlike other classical neurotropic infections, Leptospira-induced encephalopathy is mainly induced via immune-mediated mechanisms through dysregulation of glial response and peripheral immunity. The onset of infection is marked by the invasion of early innate immune clearance. There is a substantial presence of bacteremia and elevated peripheral inflammation due to the atypical engagement of pattern recognition receptors. The enhanced circulating cytokines and endothelial dysfunction cause blood-brain barrier disruption, along with the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) cascades. The subpopulations of the glial cells are the primary central nervous system (CNS) populations that undergo activation, such as microglia and astrocytes, to re-establish homeostasis. There is a positive feedback loop activation for the inflammation pathway, with exacerbated cerebral edema and neuronal dysfunction, which are characteristic of AES. The severity of neuronal parasitic disease correlated with immune dysregulation and glial activation rather than the direct Leptospira infection in the neuronal tissue. It may be proposed that the Leptospira-induced AES represents a neuroimmune disorder in which peripheral immune activation and glial-driven neuroinflammation converge to produce acute cerebral dysfunction. Understanding these interconnected pathways is essential for improving diagnosis and developing targeted therapeutic strategies for Leptospirosis/Leptospira-associated AES.