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COVID-19 is causing a global crisis and a public health emergency. Understanding COVID-19 pathophysiology in an ayurvedic host-centric framework is required for effective Ayurvedic use. According to the global epidemiology of coronavirus disease 2019 (COVID-19), clinical severity ranges from asymptomatic to fatal. Despite the fact that the clinical and laboratory characteristics of COVID-19 patients have been thoroughly studied, the pathophysiological mechanisms underlying disease severity and progression remain unknown. This review focuses on key mechanisms proposed to contribute to COVID-19 progression from viral entry to multisystem organ failure, as well as the critical role of the immune response in viral clearance or progression to death.