(1) Background: The emergence of H5N1 Influenza A viruses clade 2.3.3.4b since 2020, have caused the mortality of thousands of birds/mammals worldwide, through evolu-tionary changes have been associated with acquired mutations and posttranslational modifications. (2) Methods: This study aimed to compare the mutational profile of H5N1 avian Influenza virus isolated from a Peruvian natural reserve, with recent data from other related international studies made in human and different species of domestic and wild birds and mammals. Briefly, the near complete protein sequences of Influenza virus coming from a Calidris alba were analyzed in a multisegmented level, altogether with 55 samples collected between 2022-2024 in different countries. Moreover, the glycosylation patterns were also predicted in silico. (3) Results: A total of 603 amino acid changes were found among H5N1 viruses analyzed, underscoring the detection of critical mutations HA:143T, HA:156A, HA:208K, NA: 71S, NP:52H, PA:336M, PA:36T, PA:85A/N, PB1-F2:66S, PB2:199S, PB2:292V, PB2:559T, as well as PA:86I, PA:432I, PA:558L, HA:492D, NA:70D, NS1-83P, PB1:515A, PA-X:57Q, PB1-F2:22E, NS1-21Q, NEP:67G, among others, considered of importance under One Health perspective. Similarly, changes in the N-linked glycosylation sites (NLGs) predicted in both HA and NA proteins were found, highlighting the loss/acquisition or changes in some NLGs sites such as 209NNTN, 100 NPTT, 302NSSM (HA) and 70NNTN, 68NISS, 50NGSV (NA). (4) Conclu-sions: This study provides our understanding about the evolution of current Influenza A viruses H5N1 HPAIV circulating globally. These findings outline the importance of sur-veillance updating mutational profiles and glycosylation patterns of these highly evolved virus.