The current study aimed to investigate the influencing factors of acute stress disorder (ASD) in frontline nurses delivering care in a hospital for COVID-19 in Wuhan, China. In this cross-sectional study, 298 frontline nurses were surveyed during the first month of direct care delivery for patients with COVID-19 via the Stanford Acute Stress Reaction Questionnaire, Simplified Coping Style Questionnaire, and Multidimensional Scale of Perceived Social Support. Through logistic regression analysis, we identified the influencing factors of ASD. Our results showed that 13.8% of participants had ASD; frontline nurses were affected by ASD symptoms in different degrees; higher perceived social support from friends and colleagues were the major protective factors of ASD; and a negative coping style was a risk factor for ASD. Psychological crisis management interventions aimed at frontline nurses may be essential to prevent ASD during public health crisis events.