H6 avian influenza virus (AIV) is one of the most prevalent AIV subtypes in birds globally. To investigate the current situation and characteristics of H6 AIVs circulating in China, we analysed the epidemiology, genetic evolution and pathogenic features of this subtype. During 2000-2021, H6 subtype AIVs spread widely through Southern China and presented high host diversity. On analysing 171 H6 viruses isolated during 2009-2021, dynamic reassortments were observed among H6 and other co-circulating AIV subtypes, and these generated a total of 16 different genotypes. A few H6N6 strains possessed L226 and S228 mutations of hemagglutinin (H3 numbering), which may enhance the affinity of H6 viruses to human receptors. H6N6 viruses also exhibited divergent pathogenicity and growth profiles in vivo and in vitro. Some of the H6N6 viruses could infect mice without mammalian adaptation, and even caused death in this species. Therefore, our study demonstrated that the H6 AIVs posed a potential threat to human health and highlighted the urgent need for continued surveillance and evaluation of the H6 influenza viruses circulating in the field.