The mental health problems caused by COVID-19 pandemic to every person and every group cannot be ignored, especially for college students, who are the main force of the society. Few studies explore the mechanism of action between college students' epidemic stress perception and life satisfaction in China. The study aims to understand the association between the epidemic stress perception of COVID-19 on life satisfaction, and examines the effect of coping flexibility and perceived social support in China. We investigated 597 college students by questionnaire and found college students' epidemic stress perception of COVID-19 was significantly negatively associated with life satisfaction; coping flexibility partially mediated the relationship between college students' epidemic stress perception of COVID-19 and their life satisfaction; perceived social support moderated role in the first half of the mediating pathway. Practical strategies to improve college students' life satisfaction were discussed in the paper.