Objective: The outbreak of COVID-19 that commenced in December 2019 in Wuhan, China, has caused extensive public health concerns and posed substantial challenges to health professionals, especially for those in the center of the epidemic. The current study aimed to assess the prevalence, related factors, and mechanism of acute stress disorder (ASD) among health professionals in Wuhan during this critical period. Methods: The study used a cross-sectional design. Self-administered questionnaires were distributed to the frontline health professionals in Wuhan hospitals from January 28 to February 1, 2020. Mental health-related measurements included ASD, depression, anxiety, conflict experiences, hostility, and psychosomatic symptoms. Structural equation modeling was used to analyze the factors associated with ASD among health professionals. Results: A total of 332 frontline health professionals were included in the analysis (mean [standard deviation] age = 32.21 [8.77] years; 78.0% women). ASD was a prominent mental health problem in the health professionals surveyed, with a prevalence of 38.3%. Anxiety (24.7%) and depression (20.2%) were also common. Structural equation modeling analyses revealed that emotional distress (i.e., anxiety and depressive symptoms) fully mediated the association between conflicts with ASD (the standardized indirect coefficient β = 0.47, p = .016). The most common reported symptom was chest pain (51.2%). ASD was significantly associated with psychosomatic symptoms. The majority (67.8%) reported being easily annoyed or irritated, and ASD was associated with hostility. Conclusions: During the COVID-19 outbreak, a substantial number of health professionals in Wuhan suffered from ASD. Furthermore, ASD was found to be associated with psychosomatic symptoms as well as the hostility. The poor mental health of health professionals has detrimental impacts both on the well-being of staff in health care systems and may adversely affect the quality of patient care. We call for interventions that aim to relieve the psychological and occupational stress. Considering that most of our participants were young, female frontline health professionals, the results may not be generalized to more heterogenous samples.