In 2021–22, clade 2.3.4.4b highly pathogenic avian influenza (HPAI) viruses were introduced by wild birds into North America, leading to geographically widespread disease. In response to HPAI outbreaks throughout late 2021 and early 2022, we recorded observations of sick and dead birds, estimated abundance of carcasses, collected swab and sera samples to detect viruses, and monitored bird nesting on the Yukon-Kuskokwim Delta region of Alaska to document potential effects of disease. Thirty-six reports of sick and dead birds were registered across the region. Nineteen carcasses were opportunistically collected for diagnostic testing, of which 12 were confirmed to be infected with clade 2.3.4.4b HPAI viruses. Carcass abundance estimates from line-distance sampling provided evidence that the most common species of dead birds from the western Yukon-Kuskokwim Delta region were Cackling Goose (Branta hutchinsii minima), Glaucous Gull (Larus hyperboreus), and Black Brant (Branta bernicla nigricans). Only one paired cloacal and oropharyngeal swab sample from a Northern Pintail (Anas acuta) tested positive for clade 2.3.4.4b HPAI virus, out of 464 live-captured duck and goose samples. Of 195 sera samples from waterfowl screened for antibodies reactive to influenza A viruses, antibodies were found in 41–98% of samples collected from Emperor Goose (Anser canagicus), Cackling Goose, Black Brant, and Spectacled Eider (Somateria fischeri). In addition, 15–98% of the same sera samples were reactive to a clade 2.3.4.4b H5 antigen. Fewer Black Brant and Emperor Goose nests were found on long-term study plots during 2022 than in previous years. Collectively, we found that HPAI viruses affected at least seven species of wild birds inhabiting the region during 2022. The full scope of impacts of HPAI at this location during 2022 is unknown, but our data indicate that acute effects to avian population health on the Yukon-Kuskokwim Delta region were likely modest.