In the post-COVID-19 era, developing enduring and broad-spectrum antiviral drugs is paramount to preventing widespread outbreaks from variants of the virus and potential emerging coronaviruses. Driven by the viruses' reliance on hACE2 as the primary cellular receptor, we collaborate with Dr. I-Hsuan Wang (Institute of Biomedical Sciences at Academia Sinica) to discover a monoclonal antibody ch2H2, which exhibited a high affinity to the viral Spike protein binding site on hACE2. This antibody, without affecting the biological function of hACE2, demonstrated robust inhibitory effects against various COVID-19 viral variants in in vivo neutralization studies. Utilizing adeno-associated virus (AAV) delivery in animal experiments, a single injection resulted in sustained and high levels of ch2H2 antibodies in mice. In prophylactic administration against the Omicron variant BA.5, which led to declined vaccine effectiveness, AAV/ch2H2 significantly reduced viral loads and mitigated pulmonary pathological changes. These findings underscore the potential of AAV-delivered hACE2-blocking antibodies as a promising avenue for broad-spectrum antiviral drug development in the future.