COVID-19-related lockdown can lead to mental health problem, which displays heterogeneous between individuals. The aim of this study was to explore the association between mental health, social support and psychological capital state of professional staff with different personalities during the COVID-19 pandemic in China. A cross-section study was conducted via online survey using the questionnaires of General Health Questionnaire (GHQ-12), Multidimensional Scale of Perceived Social Support (MSPSS), Psychological Capital Questionnaire (PCQ), Eysenck Personality Questionnaire-Revision Short Scale of China (EPQ-RSC). A total of 626 employees were included. Multiple regression analysis was performed to investigate the association of psychological capital, perceived social support, EPQ-N and EPQ-E and their interactions in general mental health. About 2.7% of professionals had mental health. The married had a higher mental health score than the single (P<0.05). The regular exercising workers had the lowest mental health score (P<0.05), and higher psychological capital and social support scores than the non-exercising ones (P<0.01). Multivariate analysis showed that the interaction between social support, psychological capital and neuroticism was statistically significant (β=-0.161, P<0.001) in general mental health with neuroticism ranking the top (β=0.352, P<0.001). Mediation analysis showed that social support modified the effect of psychological capital on mental health, accounting for 25.5% of the total effect, and that both social support and psychological capital mediated the effect of neuroticism or extroversion differentially on mental health. Neuroticism is an influencing factor on mental health of professional staff. Social support and psychological capital played a partial mediating role in the effect of neuroticism or extroversion differentially on mental health in China. The findings suggest that during the COVID-19 pandemic, more social support and psychological capital are needed for the professional individuals with neuroticism to alleviate their stress and improve mental health.