A scientific understanding of the impact of COVID-19 on the psychological status of residents is important for improving medical services and responding to public health emergencies. With the help of some of the most popular network communication tools (including Wechat and Weiboand QQ), online questionnaires were completed by South China citizens during the early stage of the COVID-19 pandemic based on psychological stress theory and using a comprehensive sampling method. Through cooperation with experts from other institutions, the content of the questionnaire was designed to include interviewees’ spatial locations and individual information, identify whether negative emotions were generated, and determine the level of psychological stress and the degree of perception change, etc. According to the data type, mathematical statistics and multiple logistic regression methods were used to examine regional differentiation and influencing factors regarding the psychological stress of residents using 1668 valid questionnaires from 53 municipal administrative units in South China. The results firstly showed that over the whole area there was typical regional differentiation in South China, especially in relation to negative expression and psychological stress, with this feature reflecting the dual urban–rural structure. Secondly, regional differences were obvious. Residents of Hainan showed stronger change of psychological stress than those of the other two provinces. In contrast, Guangdong residents were the least psychological stress, and the concept of a harmonious relationship between human beings and nature was not accepted as well as in the other two provinces. Thirdly, in each province the capital city acted as the regional pole, with greater psychological status. This polarization effect decreased with greater distance, reflecting the theory of growth poles in human geography. Fourthly, gender, education level, occupation, informational correction, and the possibility of infection were notable factors that affected the psychological status of interviewees facing COVID-19. However, the functions were different and were decided by the dependent variable. Lastly, based on conclusions summarized from three perspectives, it was found that regional differentiation, public information, and social structure need to focused upon in order to handle sudden major health issues.