The global pandemic of COVID-19 disease is caused by the pathogenic factor called SARS-CoV-2. Meanwhile, a series of vaccines and small-molecule drugs, including the mRNA vaccines and Paxlovid®, have been approved, but their efficacy is decreased significantly due to the constant emergence of mutant viral strains. The R&D of host-directed therapeutics has great potential to overcome such limitations and provide new prevention and therapy options for patients with COVID-19 or high-risk group for SARS-CoV-2 infections. Transmembrane serine protease 2 (TMPRSS2) is belonging to a protein family with highly conserved serine protease domain whose crucial role in viral entry is to activate the spike protein of viruses to induce the fusion between host cells and viruses. In this review, we sketch the critical position of TMPRSS2 in the SARS-CoV-2 viral entry and summarize the advanced research and development of TMPRSS2 inhibitors, including repurposed drugs, as a new way to fight COVID-19.