To evaluate cerebral function and mental health of frontline medical staff during the COVID-19 pandemic in Wuhan. Methods: A total of 141 frontline health workers were enrolled. The Symptom Checklist-90 (SCL-90) was used to assess the mental health of the medical staff. The brain function of the medical staff was evaluated by a cerebral functional device produced by Beijing Easymonitor Tech. Results: During the COVID-19 outbreak, the total SCL-90 scores of frontline medical staff were significantly higher than scores after the pandemic [(145.4 ± 42.8) versus (131.4 ± 35.3), P<0.05)]. The positive mental symptoms (SCL-90 factors ≥2) were somatization, depression, and paranoia. Analysis of cerebral functions showed that factors such as brain metabolism rate, brain relaxation, cognitive efficiency, and mental resilience were significantly higher during the COVID-19 pandemic than after. Conclusion: The COVID-19 pandemic brought immense pressure to the frontline medical staff in Wuhan, leading to abnormal brain function and mental health disturbances.