Researchers assessed the protective ability of a chimpanzee adenovirus (simian Ad-36)-based SARS-CoV-2 vaccine (ChAd-SARS-CoV-2-S) that encodes a pre-fusion stabilized spike protein (S) in mice. Upon administering the vaccine intramuscularly, the mice exhibited protection against lung inflammation, pathology, and infection. The mice also exhibited cell-mediated and humoral immune responses upon intramuscular administration of the vaccine. However, high amounts of viral RNA of SARS-CoV-2 was still detected in the lungs of the mice after intramuscular vaccine administration. Contrastingly, upon intranasal administration of the vaccine in a single dose, significantly high amounts of neutralizing antibodies, anti-SARS-CoV-2 IgA, and T cell responses were induced, offering complete protection against SARS-CoV-2 infection in the lower and upper respiratory tracts. Thus, ChAd-SARS-CoV-2-S has a strong potential for preventing against and protecting from SARS-CoV-2 infection.