Epidemiological data shows a discrepancy in COVID‐19 susceptibility and outcomes with some regions being more heavily affected than others. However, the factors that determine host susceptibility and pathogenicity remain elusive. An increasing number of publications highlight the role of Transmembrane Serine Protease 2 ( TMPRSS2 ) in the susceptibility of the host cell to SARS‐CoV‐2. Cleavage of viral spike protein via the host cell's TMPRSS2 enzyme activity mediates viral entry into the host cell. The enzyme synthesis is regulated by the TMPRSS2 gene, which has also been implicated in the entry mechanisms of previously reported Coronavirus infections. In this review, we have investigated the pathogenicity of SARS‐CoV‐2 and disease susceptibility dependence on the TMPRSS2 gene as expressed in various population groups. We further discuss how the differential expression of this gene in various ethnic groups can affect the SARS‐CoV‐2 infection and Coronavirus disease (COVID)‐19 outcomes. Moreover, promising new TMPRSS2 protease blockers and inhibitors are discussed for COVID‐19 treatment.