The COVID-19 was taken as an example to study the mechanism of regional stigmatization —— the impact of major public health emergencies. By collecting the data of Sina Weibo, a social media platform, and using the rooted theory method, the negative comments on the major public health emergency related to the epidemic situation of new crown virus pneumonia were coded. The model of the impact of major public health emergencies on regional stigma is constructed, and the theoretical saturation test is carried out. It is found that the topic events of major public health emergencies will produce regional stigma through the attribution of responsibility and negative emotions of Internet users. In order to reduce or eliminate the negative effects of regional stigma, this study suggests that the strategy and suggestion of de-stigmatization should be adopted for different subjects and different levels.