Enduring occurrence of severe COVID-19 for unvaccinated, aged, or immunocompromised individuals remains an urgent need. Soluble human angiotensin-converting enzyme 2 (ACE2) has been used as a decoy receptor to inhibit SARS-CoV-2 infection, which is limited by moderate affinity. We describe an engineered, high-affinity ACE2 that is consistently effective in tissue cultures in neutralizing all strains tested, including Delta and Omicron. We also found that treatment of AC70 hACE2 transgenic mice with hACE2-Fc receptor decoys effectively reduced viral infection, attenuated tissue histopathology, and delayed the onset of morbidity and mortality caused by SARS-CoV-2 infection. We believe that using this ACE2-Fc protein would be less likely to promote the escape mutants of SARS-CoV-2 as frequently as did those neutralizing antibody therapies. Together, our results emphasize the suitability of our newly engineered hACE2-Fc fusion protein for further development as a potent antiviral agent against Pan-SARS-CoV-2 infection.