The outbreaks of highly pathogenic avian influenza A (H5N1) clade 2.3.4.4b in South America, which began in 2022, have had significant repercussions across the continent and have led to significant challenges in animal and public health. This review explores the virus´s transmission across South America, highlighting the spread of this panzootic through migratory birds and its severe impact on the poultry industry and various wild species, including mammals. The underreporting of influenza cases in poultry underscores the need for enhanced national regulations and strategies to promote reporting within the productive sector. Additionally, the review emphasizes the necessity for active case finding and genomic surveillance in the animal sector to manage better and control the virus. The economic and public health impacts of a potential future pandemic are also considered, emphasizing the need for strengthened surveillance strategies with the One Health approach to mitigate these risks.