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Here, we synthesize outbreak reports submitted to the World Organization for Animal Health by South American countries and overseas territories in this continent, and document the virus\u2019s unprecedented expansion into Antarctica, affecting wild birds, wild mammals, and domestic poultry. Phylogenetic and time-calibrated Bayesian analyses were performed on available genomic sequences. Over 6 million domestic birds were lost, mostly from commercial operations. Of the 11 South American countries and overseas territories that reported H5N1 to WOAH, 10 reported infections in wild birds, spanning 104 species, 59.62% of which are migratory and predominantly non-trans-equatorial. Marine mammal outbreaks followed wild bird detections, with the South American sea lion (Otaria flavescens) being the most reported species. Several Antarctic bird species with migratory behavior were also reported in South America. Genomic analyses revealed multiple introduction events, regional viral diversification, and patterns consistent with repeated cross-species spillover events. These findings highlight H5N1\u2019s extensive ecological reach in the Southern Hemisphere and underscore the urgent need for a One Health approach that strengthens wildlife and backyard-poultry surveillance, alongside coordinated regional action to control and prevent further HPAI spread.<\/jats:p>","DOI":"10.3390\/v18070764","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T09:51:09Z","timestamp":1783936269000},"page":"764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Highly Pathogenic Avian Influenza H5N1 in South America, 2022\u20132025: Spread, Affected Species, and Southward Expansion into the Antarctic Region"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6117-6576","authenticated-orcid":false,"given":"Fernanda","family":"S\u00e1nchez-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"One Health Institute & PhD Program in Conservation Medicine, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370251, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanza","family":"Diaz-Gavidia","sequence":"additional","affiliation":[{"name":"Escuela de Medicina Veterinaria, Facultad de Medicina, Facultad de Ciencias Biol\u00f3gicas y Facultad de Agronom\u00eda y Sistemas Naturales, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7820436, Chile"},{"name":"SENTINET, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soledad","family":"Ru\u00edz","sequence":"additional","affiliation":[{"name":"Escuela de Medicina Veterinaria, Facultad de Recursos Naturales y Medicina Veterinaria, Universidad Santo Tom\u00e1s, Santiago 8370003, Chile"},{"name":"Centro Bah\u00eda Lomas, Facultad de Ciencias, Universidad Santo Tom\u00e1s, Puerto Montt 5400000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Jimenez-Bluhm","sequence":"additional","affiliation":[{"name":"Escuela de Medicina Veterinaria, Facultad de Medicina, Facultad de Ciencias Biol\u00f3gicas y Facultad de Agronom\u00eda y Sistemas Naturales, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7820436, Chile"},{"name":"SENTINET, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a038398","DOI":"10.1101\/cshperspect.a038398","article-title":"Structure and function of the influenza virus transcription and replication machinery","volume":"10","author":"Fodor","year":"2020","journal-title":"Cold Spring Harb. 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