A 2023 outbreak of highly pathogenic avian influenza A(H5N1) in Argentina affected marine mammals, including sea lions and fur seals, and possibly seabirds. The virus, belonging to clade 2.3.4.4b, was first detected in a wild goose near the Chilean border and later spread to sea lions in Río Grande, Argentina. Full-genome sequencing of samples from affected animals revealed that the virus was closely related to strains circulating in South America during 2022–2023. Phylogenetic analysis showed that the viruses from Punta Bermeja, a major sea lion colony, did not cluster with those from the initial goose detection but were closely related to viruses from sea lions in Chile and Peru, suggesting a separate introduction into Argentina. The viruses contained mammalian adaptation mutations, such as Q591K and D701N in the polymerase basic 2 gene, which are associated with increased pathogenicity in mammals. These mutations were also present in a virus isolated from a human in Chile, highlighting the potential public health threat posed by these viruses. The study supports the hypothesis that HPAI H5N1 viruses spread from North America to South America, with subsequent transmission among pinnipeds. The rapid spread and high mortality in pinnipeds suggest that pinniped-to-pinniped transmission may have played a role in the spread of the virus. The findings underscore the importance of monitoring the spread of HPAI H5N1 in marine mammals and the potential for spillover to humans.A 2023 outbreak of highly pathogenic avian influenza A(H5N1) in Argentina affected marine mammals, including sea lions and fur seals, and possibly seabirds. The virus, belonging to clade 2.3.4.4b, was first detected in a wild goose near the Chilean border and later spread to sea lions in Río Grande, Argentina. Full-genome sequencing of samples from affected animals revealed that the virus was closely related to strains circulating in South America during 2022–2023. Phylogenetic analysis showed that the viruses from Punta Bermeja, a major sea lion colony, did not cluster with those from the initial goose detection but were closely related to viruses from sea lions in Chile and Peru, suggesting a separate introduction into Argentina. The viruses contained mammalian adaptation mutations, such as Q591K and D701N in the polymerase basic 2 gene, which are associated with increased pathogenicity in mammals. These mutations were also present in a virus isolated from a human in Chile, highlighting the potential public health threat posed by these viruses. The study supports the hypothesis that HPAI H5N1 viruses spread from North America to South America, with subsequent transmission among pinnipeds. The rapid spread and high mortality in pinnipeds suggest that pinniped-to-pinniped transmission may have played a role in the spread of the virus. The findings underscore the importance of monitoring the spread of HPAI H5N1 in marine mammals and the potential for spillover to humans.