Background: Healthcare professionals (HCPs) working to save lives during the coronavirus disease 2019 (COVID-19) pandemic are under tremendous physical and psychological pressure, therefore facing the risk of developing challenges with mental health.Aim: This study aimed primarily to determine the prevalence and factors associated with depression, anxiety and stress among HCPs in a tertiary hospital in Lagos State during the COVID-19 pandemic.Setting: Lagos State University Teaching Hospital (LASUTH), Ikeja, Lagos, Nigeria.Methods: This was a descriptive cross-sectional study conducted between June and July 2021 among 1452 doctors and nurses in LASUTH, Ikeja, Lagos, Nigeria, selected by the multistage sampling method. Depression, anxiety and stress were assessed using the Patient Health Questionnaire, Generalised Anxiety Disorder and Perceived Stress Scale, respectively.Results: The majority of respondents were female (72.5%), with two-thirds being nurses. The prevalence of depression, anxiety and stress was 9.8%, 5.0% and 62.4%, respectively. Nurses showed a higher prevalence of these mental health conditions as compared with doctors. Younger HCPs, nurses, those that lost a colleague to COVID-19, and those whose family members were infected with COVID-19 were more likely to be depressed. Nurses and those afraid of being infected were more likely to experience anxiety. Younger HCPs, nurses, history of anxiety and/or depression and previous COVID-19 infection were identified as factors associated with stress.Conclusion: Stress was the most prevalent mental health condition with nurses being the most affected of the HCPs and at a greater risk of developing challenges with mental health. Psychosocial interventions and stress management techniques are recommended to minimise the risks.Contribution: This study adds to the few studies on the mental health of HCPs during COVID-19 and calls for in-depth surveys to understand psychosocial challenges among HCPs in Nigeria.