Background After the occurrence of public health emergencies, people will have a series of physiological reactions, which will develop into psychological stress disorder in serious cases. Based on this, the purpose of this study is to analyze the psychological stress response and intervention countermeasures of exposed people under sudden public health crisis. Objective To explore the psychological stress response and intervention countermeasures of exposed population under sudden public health crisis. Methods A total of 400 people under the sudden public health crisis that bring about serious damage to public health, mass diseases of unknown causes, major food and occupational poisoning, and other events that seriously affect public health from December 2020 to December 2021 were selected as the subjects of the study. It was randomly and equally divided into two groups to take different intervention measures, the control group was given routine public health crisis intervention measures, and the research group was given comprehensive intervention. The metabolism, social function defects, health symptoms, psychological status, quality of life, sleep quality, and stress reaction were compared between the two groups. Results The rate of good metabolism in the research group was significantly higher than that in the control group (P < 0.05). After intervention, the scores of Social Disability Screening Schedule (SDSS) and Symptom Checklist 90 (SCL-90) decreased in both groups, and the scores of SDSS and SCL-90 in the research group were lower than those in the control group. After intervention, the scores of self-rating depression scale and self-rating anxiety scale in the two groups decreased, and the scores of self-rating depression scale and self-rating anxiety scale in the research group were lower than those in the control group (P < 0.05). The sleep quality of the research group was better than that of the control group (P < 0.05). The stress response indexes such as cortisol, blood glucose, and C-reactive protein in the two groups were decreased after intervention. The stress response indexes such as cortisol, blood glucose, and C-reactive protein in the research group were lower than those in the control group (P < 0.05). Conclusion Giving that comprehensive intervention measures to people exposed to sudden public health crisis can effectively relax their stress response, reinvigorate their quality of life and sleep, reduce depression and anxiety, and improve their metabolism, therefore, in the case of the outbreak of public health crisis in the future, it is worth applying for reference and popularizing.