This study investigated the buffering role of hope between perceived stress and health outcomes among front-line medical staff treating patients with suspected COVID-19 infection in Shenzhen, China. In the cross-sectional study with online questionnaires, medical staff's perceived stress, anxiety, depression, sleep quality, and hope were measured by the 10-item Chinese Perceived Stress Scale, Hospital Anxiety and Depression Scale, the Pittsburgh Sleep Quality Index, and the Locus-of-Hope Scale, respectively. A total of 319 eligible front-line medical staff participated. The prevalence of anxiety (29.70%), depression (28.80%), poor sleep quality (38.90%) indicated that a considerable proportion of medical staff experienced mood and sleep disturbances during the COVID-19 pandemic. Internal locus-of-hope significantly moderated the effects of stress on anxiety, depression, and sleep quality. Moreover, external family locus-of-hope and external peer locus-of-hope significantly moderated the association between perceived stress and depression. The prevalence of symptoms indicates that both mental and physical health outcomes of front-line medical staff deserve more attention. Internal and external locus-of-hope functioned differently as protective factors for medical staffs' health and might be promising targets for intervention.