The COVID-19 pandemic was a stressful event for all. It threatened people's physical and mental health. Previous studies have found that resilience can help people deal with stress and difficulties more effectively and prevent them from mental health problems. Coping style mediates the relationship between resilience and psychological well-being. Given the novelty and recency of the COVID-19, it is unknown whether resilience can also protect individuals in new difficulties, and whether the previous effective coping styles can be applied to new situations. The current study aimed to explore the influence mechanism of college students' resilience on negative stress response during the pandemic, and the chain mediation of coping style and positive adaptive response. A questionnaire survey was conducted among 910 college students (M = 20.58 years; 41.1% men, 58.9% women) studying in Shanghai by stratified random cluster sampling. At that time, they were in 27 different provinces and cities because of the COVID-19 pandemic lockdown. The research tools included Connor-Davidson Resilience Scale (CD-RISC), Simplified Coping Style Questionnaire (SCSQ), Positive Adaptive Response Questionnaire (PARQ), and Negative Stress Reaction Questionnaire (NSRQ). The results showed that: (1) College students' resilience, coping style, positive adaptive response and negative stress reaction were significantly correlated with each other; (2) Resilience could not directly affect negative stress reaction, but it could affect negative stress reaction through the chain mediation of coping style and positive adaptive response. These findings suggest that resilience enhancement intervention programs need to focus on the cultivation of individual positive coping style; In response to major emergencies such as the COVID-19 pandemic, officials can help people reduce negative stress reaction by disseminating positive coping strategies through the media.