The H5N1 clade 2.3.4.4b avian influenza virus outbreak in poultry and dairy cattle is a potential pandemic threat for humans. A safe and effective H5N1 influenza vaccine will be needed if the virus acquires the capacity for efficient human-to-human transmission and may also be useful as a veterinary vaccine. In this study, we demonstrate robust vaccine protection in a lethal model of H5N1 clade 2.3.4.4b influenza infection in cynomolgus macaques. We vaccinated 24 cynomolgus macaques with mRNA or rhesus adenovirus serotype 52 (RhAd52) vaccines expressing the hemagglutinin (HA) from H5N1 clade 2.3.4.4b by the intramuscular or intratracheal route and challenged them with the H5N1 human isolate hu-TX37-H5N1. Of sham control animals, 83% (five of six) developed severe rapidly progressive consolidative pneumonia and were euthanized by days 5 to 7 after challenge. In contrast, 100% (17 of 17) of vaccinated macaques survived and controlled virus replication to undetectable titers in both the upper and lower respiratory tracts by days 4 to 14 after challenge. Mucosal boosting with the RhAd52 HA vaccine generated robust mucosal antibody and T cell responses and afforded 6.3 and 5.1 log10 median viral load reductions in viral RNA with no detectable infectious virus titers compared with sham controls in bronchoalveolar lavage and nasal swabs, respectively. These data demonstrate that an adenovirus-vectored vaccine can protect against lethal H5N1 clade 2.3.4.4b challenge in nonhuman primates and further highlight the importance of vaccine-elicited mucosal immunity.