With the success of viral-vectored vaccines against Ebola and SARS-CoV-2, these platforms are now established as promising tools for biodefence against outbreak pathogens. Here, we report the development of adenoviral-vectored vaccines against plague, caused by Yersinia pestis. Replication-deficient adenoviral-vectored constructs expressing the protective Y. pestis antigens F1 and LcrV, alone or in combi and combinations thereof were created. Expression of the antigens was confirmed in vitro, and immunogenicity assessed in mice. Protective efficacy was evaluated using a virulent Y. pestis aerosol challenge model in mice. All vaccine candidates induced high serum IgG antibody responses. Notably, the antibody responses were similar when vectors expressing different antigens were mixed or when using a single vector expressing a chimeric fusion of the two antigens. All of the six experimental vaccine formulations tested via intramuscular injection containing either the V gene or purified V protein provided 90%-100% protection from mortality due to inhalational infection with Y. pestis. Notably, only the human adenovirus 5 construct expressing a full length F1-V fusion provided 100% protection from both morbidity and mortality after a single dose. In contrast, naive mice and 50% of mice immunized with two doses of the recombinant proteins with adjuvant displayed clinical signs of illness (morbidity) despite protection from mortality. Importantly, in a follow-up virulent aerosol challenge study, a single dose of ChAdOx1 F1-V fusion provided protection comparable to that achieved with HuAd5 vaccine. Based on these results, a ChAdOx1 F1-V fusion vaccine has progressed to phase I human clinical trials.