BACKGROUND: An epizootic of highly pathogenic avian influenza A (H5N1) has spread worldwide since 2022. Even though this virus has been extensively studied for many decades, little is known about its evolution in South America. METHODS: Here, we describe the sequencing and characterization of 13 H5N1 genomes collected from wild birds, poultry, and wild mammals in Peru during the genomic surveillance of this outbreak. RESULTS: The samples belonged to the highly pathogenic avian influenza (H5N1) 2.3.4.4b clade. Chilean and Peruvian samples clustered in the same group and therefore share a common ancestor. An analysis of the hemagglutinin and neuraminidase genes detected new mutations, some dependent upon the host type. CONCLUSIONS: The genomic surveillance of highly pathogenic avian influenza is necessary to promote the One Health policy and to overcome the new problems entailed by climate change, which may alter the habitats of resident and migratory birds.