This study sought to explore the effects of COVID-19 exposure, pandemic-related appraisals and coping strategies on psychological symptoms among the front-line healthcare workers based on the transactional theory of stress and coping. A cross-sectional study was conducted in a Wuhan hospital designated for inpatients with COVID-19, assessing COVID-19 exposure (whether or not exposed to confirmed patients at workplace), psychological symptoms, appraisals, and coping strategies in 311 participants. Results revealed that the pandemic markedly affected healthcare workers' mental well-being through appraisal and coping, with 38.9% reporting high levels of psychological symptoms. Primary appraisal related closely with COVID-19 exposure, especially in female, while secondary appraisal was associated with problem-focused coping. Both problem-focused and emotion-focused coping had a protective effect against psychological symptoms, but also showed gender differences in its relations with other variables. These findings could potentially benefit to enrich relevant theories, and to develop psychological programs for future epidemics.