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Background The social distancing during COVID-19 is likely to cause a feeling of alienation, which may pose a threat to the public's mental health. Our research aims to examine the relationship between negative emotions and Post-Traumatic Stress Disorder (PTSD), considering the mediation effect of alienation and how it is moderated by anxiety and depression. Methods For this, the current study conducted a cross-sectional survey on 7145 participants during the outbreak of COVID-19, via online questionnaires comprised of a self-designed Negative emotions questionnaire, Symptom Check List 90 (SCL-90), PTSD Checklist-civilian version (PCL-C), and Adolescent Students Alienation Scale (ASAS). Results A total of 6666 pieces of data from the general population were included in the statistical analysis. The descriptive statistics showed a relatively mild level of mental disorders. Besides, results of Conditional Process Model analysis supported our hypotheses that negative emotions and alienation were both predictors for PTSD symptoms, and their direct and indirect effects were all moderated by the level of anxiety. Limitations This study was limited by the generality and causality of the conclusion. The moderating effect of depression was left for further study due to the collinearity problem of variables. Conclusions Social distancing may have an impact on individuals' mental health by the feeling of alienation, which was moderated by affective disorders. Clinical psychologists should identify individuals' particular cognition and mental disorders to provide a more accurate and adequate intervention for them. [ABSTRACT FROM AUTHOR]