Five novel H5N6 influenza viruses, including four highly pathogenic avian influenza viruses and one low pathogenic avian influenza virus, were isolated from migratory birds in Ningxia, China in November 2017. To understand the genetic origination of the novel H5N6 virus, and the infectivity and pathogenicity of the four highly pathogenic avian influenza viruses in mammals, phylogeographic analyses and infection studies in mice were performed. The phylogenetic and phylogeographic analyses showed that the H5N6 isolates, which are closely related to the viruses from Korea, Japan and the Netherlands, originated from ressortant virus between H5N8 and HxN6 viruses from Western Russia. The animal study revealed that the SBD-87 isolate presented moderate virulence in mice, suggesting a potential public risk to humans and a potential threat to public health.