The literature shows the negative psychological impact of the coronavirus disease 2019 (COVID-19) outbreak on frontline healthcare workers. However, few are known about the mental health of physicians and nurses working in general hospitals during the outbreak, caring for patients with COVID-19 or not. This survey assessed differences in mental health in physicians and nurses working in COVID-19 or non-COVID-19 medical care units. A cross-sectional mixed-mode survey was used to assess burnout, insomnia, depression, anxiety, and stress. A total of 1,244 physicians and nurses from five general hospitals in Belgium, working in COVID-19 care units (CCU), non-COVID-19 care units (NCCU), or both (CCU + NCCU) were informed of the study. Six hundred forty-seven healthcare workers participated in the survey (response rate = 52%). Validated instruments were used to assess the outcomes: the (burnout/professional fulfillment), the (insomnia), and the (depression, anxiety, and stress). Results showed high prevalence of burnout, insomnia, depression, and anxiety among participants. After adjusting for confounders, multivariate analysis of variance showed no differences between CCU, NCCU, and CCU + NCCU workers. Univariate general linear models showed higher level of burnout, insomnia, and anxiety among nurses in comparison to physicians. Being a nurse, young, isolated, with an increased workload were risk factors for worse mental health outcomes. The mental health of the tested sample, before the outbreak, is unknown. Moreover, this cross-sectional design provides no information on the evolution of the mental health outcomes over time. Directly caring for patients with COVID-19 is not associated with worse mental health outcomes among healthcare workers in general hospitals. High prevalence of burnout, insomnia, depression, and anxiety among physicians and nurses requires special attention, and specific interventions need to be implemented. ClinicalTrials.gov, identifier NCT04344145.