Hantavirus infections are primarily acquired through inhalation of aerosolized particles originating from rodent excreta and lead to severe pulmonary and renal syndromes. Although clinical features are well characterized, tissue-level mechanisms remain unclear. Histopathology consistently shows endothelial swelling, edema, and immune cell infiltration, indicating combined viral and host immune contributions to disease pathogenesis. The lungs and kidneys are the principal target organs, where microvascular dysfunction drives the most severe clinical manifestations. Hantaviruses preferentially infect endothelial cells of the microvasculature in these organs through integrin-mediated entry. Following infection, viral replication proceeds without marked cytopathic effects; instead, disruption of endothelial junctional proteins and cytoskeletal remodeling leads to progressive loss of barrier integrity. This results in increased vascular permeability, plasma leakage, and tissue edema. Activation of signaling pathways such as VEGF and RhoA/ROCK further amplifies endothelial dysfunction, contributing to pulmonary edema and renal impairment. In parallel, immune-mediated mechanisms play a central role in tissue injury. Recruitment of macrophages and cytotoxic T cells, together with elevated levels of proinflammatory cytokines including TNF-α and IL-6, intensifies vascular leakage and exacerbates organ damage. Disease severity appears to correlate more strongly with the magnitude of the host immune response than with direct viral cytotoxicity, emphasizing the importance of immunopathology in disease progression. From a mechanistic and translational perspective, hantavirus disease represents a paradigm of combined endothelial and immune-driven injury. The disruption of vascular integrity identifies potential therapeutic targets aimed at stabilizing endothelial junctions and modulating permeability-related signaling pathways such as VEGF and RhoA/ROCK. In addition, strategies that selectively attenuate excessive cytokine responses without inducing broad immunosuppression may reduce tissue damage and improve clinical outcomes. Histopathological features including endothelial swelling, tubular necrosis, and interstitial hemorrhage further provide measurable biomarkers for evaluating disease severity and therapeutic efficacy, bridging mechanistic insights with clinical application and supporting the development of targeted interventions.