Avian influenza (AI) H5N6 has replaced H5N1 as the predominant strain, and the increasing number of cases and complex recombination patterns pose significant threats to human health. The data were collected on human cases of AI H5N6 from the National Surveillance of Notifiable Infectious Disease Programme (NSNIDP) in Guangxi and used MEGA software to conduct phylogenetic analysis with published reference strains obtained from the GISAID database. Between January 1 and December 31, 2021, 11 cases of human AI H5N6 infection were reported in Guangxi. All HA genes belonged to clade 2.3.4.4, with only one virus belonging to 2.3.4.4h and the remaining viruses falling into 2.3.4.4b. Phylogenetic analysis of the genes was conducted, and some substitutions were detected in the HA gene, M1 protein, and NS1 protein. A close relationship between Guangxi viruses and AIVs of poultry origin has been observed. Given the contamination of live poultry markets and backyard poultry, AI H5N6 variants and genotypes will continuously emerge; therefore, enhancing surveillance is crucial for pandemic preparedness.