Objective To investigate the cluster spectrum and functional-associated mutation characteristics of the neuraminidase (NA) gene of A (H3N2) viruses in Tangshan, Hebei Province from 2010 to 2024. Methods A total of 30 influenza A (H3N2) virus strains in Tangshan from 2010 to 2024 were selected, which was based on the seasonal distribution of influenza sample collection. Phylogenetic tree of NA gene was constructed, and BioEdit was used for alignments of amino acid sequences to identify variations on functional-associated sites. Homologous models for B.4.3 subgroup and A/Darwin/9/2021 were constructed to analyze the conformational variation at mutation sites. Results From 2010-2024, influenza A (H3N2) virus strains in Tangshan, Hebei were divided into eight branches: A, A.2, A.2.1, A.2.2, B, B.1.1, B.4, and B.4.3. The strains in subgroups B, B.4 and B.4.3 appeared from 2023 to 2024. The NA protein antigen epitopes, resistance sites, and potential glycosylation sites all had amino acid mutations. The homologous model analysis of NA functional-associated regions of B.4.3 subgroup and A/Darwin/9/2021 revealed spatial conformation changes in amino acid 83, 150 and 331, which could influence the functional performance of associated sites. Conclusion The NA gene of influenza A (H3N2) viruses in Tangshan continues to mutate at functional sites. Mutational analysis and structural modeling indicate potential antigenic drift and drug-resistant mutations. In the future, attention should be paid to the variation trend of epidemic strains under branch B.4.3.