Influenza A(H3N2) remains a significant public health threat due to its rapid antigenic drift, which often compromises vaccine effectiveness. This study characterized the molecular and epidemiological profile of hemagglutinin (HA) variants circulating in Western Mexico throughout 2022. Among 476 positive cases, A(H3N2) was the predominant subtype (88%), with infection peaks during epidemiological weeks (EW) 1, 45, and 46. Sanger sequencing of the HA gene identified 64 amino acid substitutions, with 85.9% of the substitutions located in the HA1 subunit, primarily within the receptor-binding domain (RBD). Homology modeling and molecular docking were performed on five representative variants: C156S, D158N, Y159N, C136S, and L227P. All variants exhibited a slight decrease in binding affinity for sialic acid compared to the 1HGE reference. Notably, while mutations such as D158N and Y159N remodeled the interaction network, Glu190 and His183 remained critical for stabilizing the HA-ligand complex through hydrogen bonds and non-covalent interactions in the structural models. These structural findings suggest that contemporary mutations in the RBD may contribute to changes in receptor-binding interactions while preserving key structural features associated with host cell attachment.