The H5N1 highly pathogenic avian influenza (HPAI) virus has caused severe global losses, reaching South America in 2022 and Antarctica in 2024. Here we synthesize outbreak reports submitted to the World Organization for Animal Health (WOAH) by South American countries and document the virus´s unprecedented expansion into Antarctica, affecting wild birds, wild mammals, and domestic poultry. More than 6 million domestic birds died or were culled, mostly from commercial operations. Of the 11 South American countries 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 cases occurred after wild bird detections, with the South American sea lion (Otaria flavescens) most affected, and several Antarctic bird species with migratory behavior were also reported in South America. To complement outbreak data, we examined available genomic sequences through phylogenetic and time-calibrated Bayesian analyses, which revealed multiple introduction events, viral diversity across regions, and evidence of interspecies transmission dynamics. These findings highlight the extensive ecological reach of H5N1 in the Southern Hemisphere and underscore the urgent need for a One Health approach that strengthens wildlife and backyard-poultry surveillance while fostering coordinated regional action to control and prevent further spread of HPAI.