Highly pathogenic avian influenza H5N6, an acute infectious poultry disease, has appeared in China since 2014. The serious HPAI H5N6 epidemic has caused substantial economic losses to the poultry industry and seriously threatened public health. This study developed two maximum entropy models based on highly pathogenic avian influenza virus H5N6 surveillance data obtained through China’s national surveillance program and HPAI H5N6 outbreak data in China, identified risk factors for the disease and developed risk prediction maps. Both models had a good predictive performance with area under the receiver operating characteristic curves of 0.931 and 0.892. Our study considered 26 variables from bioclimate, geographical, and socioeconomic factors. After the screening, 14 variables were retained and incorporated into the construction of the two models. HPAIV H5N6 presence was related to population density, road density, poultry market density, mean diurnal range, and chicken density. HPAI H5N6 poultry outbreaks were associated with population density, road density, mean diurnal range, precipitation of the driest month, and chicken density. Overall, Southern China was the high-risk area for HPAIV H5N6 maintenance and H5N6 outbreak. The risk factors and maps associated with the HPAIV H5N6 presence and HPAI H5N6 outbreak identified in our study will help develop appropriate HPAIV H5N6 control measures to reduce the risk of infection and morbidity in poultry and humans.