The outbreak of COVID-19 epidemic has increased work demands for medical staff and has a certain impact on their mental health. The present study aimed to examine the role of perceived stress and social support in explaining the association between the occupational stressors and three mental health symptoms (i.e., anxiety, depression, and insomnia) of frontline medical staff. Five hundred twenty five frontline medical staff were investigated online after the outbreak of the COVID-19 (16 February, 2020–2 March, 2020) in China. The results found that the prevalence of anxiety, depression, and insomnia among frontline medical staff were 39.8, 29.9, and 37.9%, respectively. Occupational stressors were associated with anxiety, depression, and insomnia symptoms. Perceived stress significantly mediated this link. Social support moderated the second half of the indirect effect of occupational stressors on anxiety and depression symptoms. Under the epidemic situation of COVID-19, for frontline medical staff, high perceived stress and low social support may increase vulnerability for mental health symptoms triggered by occupational stressors. Thus, improving the social support and promoting the cognitive reappraisal of perceived stress may help to maintain mental health among medical staff.