Orthohantaviruses are zoonotic pathogens belonging to the family Hantaviridae and are responsible for significant human disease. These infections are characterized by acute systemic illness, vascular dysfunction, and, in severe cases, hemorrhage and multiorgan failure. Depending on the viral species involved, infection may result in hemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS), both of which are associated with substantial morbidity and mortality. Rodents act as natural reservoirs, maintaining viral persistence in endemic ecosystems and enabling sporadic spillover to humans through exposure to infected excreta or contaminated environments. This review synthesizes current knowledge on rodent reservoir competence, hantavirus replication strategies, pathogenesis, clinical manifestations, ecological drivers of transmission, public health implications and future therapeutic developments and challenges. Understanding these mechanisms is essential for enhancing surveillance, risk assessment, and preventive strategies against orthohantavirus infections.