Prophylaxis against COVID-19 is greatly needed for vulnerable populations who have a higher risk of developing severe disease. Vaccines and neutralizing antibodies against SARS-CoV-2 are currently the main approaches to preventing the virus infection. However, the constant mutation of SARS-CoV-2 poses a huge challenge to the effectiveness of these prophylactic strategies. A recent study suggested that downregulation of angiotensin-converting enzyme 2 (ACE2), the receptor of SARS-CoV-2 entry into human cells, can decrease susceptibility to viral infection in vitro, in vivo, and in human lungs and livers perfused ex situ. These findings indicate the potential to use agents to reduce ACE2 expression to prevent COVID-19, but the efficacy and safety should be verified in clinical trials. Considering ACE2 performs physiological functions, risks due to its downregulation and benefits from prophylaxis against SARS-CoV-2 infection should be carefully weighed. In the future, updating vaccines against variants of SARS-CoV-2 might still be an important strategy for prophylaxis against COVID-19. Soluble recombinant human ACE2 that acts as a decoy receptor might be an option to overcome the mutation of SARS-CoV-2.