Background: To analyze the impact of the flood disasters, social support and personality on the mental health of residents in Henan Province, China, providing fundamental knowledges for making measuring strategies to improve the psychological protection and anti-stress ability of the residents after the disaster. Material and Methods: A cross-section study was conducted via an online survey platform “questionnaire star,” which included 572 residents in Henan Province, which underwent the history of ever flood disaster on July 20. The questionnaires of Impact of Event Scale-Revised Edition (IES-R), Perceived Social Support Scale (PSSS), the Depression Anxiety Stress Scales (DASS-21) and the scales of Eysenck Personality Questionnaire-Revised (EPQ-R) version in Chinese were also administered to each participant. Generalized linear regression model was performed. Results: The residents who live in the flooding areas, are male and married had a significantly higher post-traumatic stress disorder (PTSD) score than their counterparts. The scores of depression-anxiety-stress in the residents with stable emotion were significantly lower than those with unstable emotion (p < 0.001). Machine learning showed that PTSD ranked the top risk factor, followed by neuroticism for Depression-Anxiety-Stress after disaster. The PTSD was negatively correlated with social support (p < 0.01), while it was positively correlated with depression-anxiety-stress and emotional stability (p < 0.01). There was a statistically significant interaction between PTSD, social support and neuroticism on depression-anxiety-stress (p < 0.001), with an independent effect of 1.4% on depression-anxiety-stress. Emotional stability showed the largest association with depression-anxiety-stress. Conclusions: Residents living in the catastrophic flooding areas had significant post-traumatic mental health issues, and the severity of mental problems was differently affected by post-traumatic stress disorder and social support in individuals with different personalities. Introvert and PTSD were the major risk factors for depression-anxiety-stress after the disaster. Med Pr. 2022;73(4):305–14