Hantaviruses, members of the Hantaviridae family, are zoonotic pathogens characterized by distinct clinical syndromes, primarily manifested as hemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS). While the clinical presentation varies geographically and by viral strain, a unifying theme in hantavirus pathogenesis is that disease severity is driven less by direct viral cytotoxicity and more by profound dysregulation of host immune and vascular responses. This review explores the complex interplay between viral tropism, endothelial dysfunction, and excessive host immune activation. Hantaviruses exhibit strong tropism for endothelial cells, macrophages, and epithelial cells. Crucially, infection induces functional barrier disruption rather than overt structural destruction. This endothelial hyper-responsiveness is mediated by an interconnected network of pro-inflammatory cytokines—including TNF-α, IL-6, and IFN-γ—alongside VEGF-dependent signaling and the activation of bradykinin and complement cascades. These pathways collectively destabilize endothelial junctions, promote vascular permeability, and exacerbate tissue edema and hypotension, which are hallmarks of severe disease. The observation that hantavirus-induced vascular leakage is primarily an immune-mediated phenomenon underscores the critical need for moving beyond traditional antiviral strategies. By characterizing the mechanistic bridge between innate immune activation and endothelial integrity, this paper highlights promising avenues for host-directed therapeutic interventions. Targeted modulation of cytokine signaling, vascular-protective agents, and pathways governing endothelial permeability offer potential strategies to mitigate severe outcomes. As the burden of hantavirus infection evolves due to ecological and environmental shifts, integrating molecular virology, vascular biology, and clinical immunopathology becomes essential. Such a multi-dimensional approach is necessary to refine our understanding of disease progression and to develop more effective, translational therapeutics that preserve vascular homeostasis and limit the morbidity associated with these persistent zoonotic threats.