Between 2022 and 2025, high pathogenicity avian influenza (HPAI) H5N1 clade 2.3.4.4b was detected in poultry and wildlife across most countries in Central and South America. The epizootic peaked in 2023, subsided in 2024, and resurged in 2025. In Central America, outbreaks in wildlife were few and small, and mostly affected pelicans. In contrast, South America experienced unprecedented mass mortality in colonial seabirds and pinnipeds, including endangered and endemic species. Notably, viral adaptation enabled mammal-to-mammal transmission in pinnipeds and rapid viral spread across multiple countries along the Pacific and Atlantic coasts. Subsequent introductions to subantarctic islands and Antarctica stemmed from South American viruses. In February 2025, a novel reassortant virus emerged, recombining HPAI H5N1 B3.2 genotype with South American low pathogenicity avian influenza viruses. In May 2025, HPAI H5N1 viruses re-emerged in Brazil, causing a series of outbreaks in poultry and wild birds. The ongoing circulation and evolution of HPAI H5N1 in this region underscores the need for strengthened surveillance, expanded genomic monitoring, and enhanced integration of wildlife conservation and environmental sectors in regional response frameworks.