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The recent COVID\u201019 pandemic highlights the urgent need for novel and effective antiviral agents. The host cell protease, transmembrane serine protease 2 (TMPRSS2), facilitates viral pathogenesis by playing a critical role in viral invasion and disease progression. This protease is coexpressed with the viral receptors of angiotensin\u2010converting enzyme 2 (ACE2) for SARS\u2010CoV\u20102 in the human respiratory tract and plays a significant role in activating viral proteins and spreading. TMPRSS2 activates the coronavirus spike (S) protein and permits membrane fusion and viral entry by cleaving the virus surface glycoproteins. It also activates the hemagglutinin (HA) protein, an enzyme necessary for the spread of influenza virus. TMPRSS2 inhibitors can reduce viral propagation and morbidity by blocking viral entry into respiratory cells and reducing viral spread, inflammation, and disease severity. This review examines the role of TMPRSS2 in viral replication and pathogenicity. It also offers potential avenues to develop targeted antivirals to inhibit TMPRSS2 function, suggesting a possible focus on targeted antiviral development. 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