Highly pathogenic H5N1 avian influenza (clade 2.3.4.4b) has spread widely among dairy cattle herds since early 2024, causing major economic losses. This zoonotic event emphasizes the urgent need for H5 vaccines eliciting strong, durable, cross-reactive immune responses in cows. To address this, we immunized mice and cattle with a centralized consensus H5 vaccine, localizing near the central node of the human H5 phylogenetic tree. The vaccine was delivered using serotype-switched adenoviral vectors in a prime–boost regimen, combined with intramuscular and intranasal coadministration to target systemic and mucosal immunity and elicit strong humoral and cellular immune responses. This approach strategically integrates multiple innovative features: centralized consensus immunogens, mucosal targeting, and vector serotype switching aimed at maximizing immune protection against H5N1 viruses. Our results show that vaccination elicits strong humoral and cellular immunity in both mice and calves. In challenge experiments, vaccinated mice were fully protected against lethal infection with divergent H5N1 strains, including A/bovine/Ohio/B24OSU-439/2024. Vaccine-induced immunity was consistent across species, supporting the translatability of the mouse model findings to cattle. Overall, our findings represent a promising approach for immunizing key livestock, including cattle, against highly pathogenic avian influenza H5N1, mitigating agricultural losses, and reducing the risk of zoonotic transmission.