First identified as belonging to the H5N1 subtype in Guangdong province, China, in 1996, the Gs/GD lineage H5 avian influenza viruses have continuously evolved and spread since. H5 subtype viruses evolved into multiple distinct subclades, among which 2.3.4.4 has become dominant in China, and H5N6 viruses of this subclade led to an apparent increase in human infections in 2021 and 2022. During this period, 33 cases (of a total of 76 recorded cases infected with subclade 2.3.4.4 H5N6 viruses) have been documented, resulting in 11 deaths and posing an alarming threat to public health. Almost all confirmed cases were in individuals who had reported exposure to poultry. To address concerns regarding the sharp increase in the number of human infections, we explored the evolutionary dynamics and conducted a risk assessment of H5N6 viruses from birds in live poultry markets during 2021.