BACKGROUND The COVID-19 pandemic has placed immense pressure on healthcare workers (HCWs). OBJECTIVE This study sought to find the prevalence and factors associated with psychological distress among HCWs in South Africa during the beginning phases of COVID-19 and make relevant recommendations. METHODS The survey was administered online through a data-free platform. Data were benchmarked to the national population of over 500 000 healthcare professionals in South Africa. Multiple logistic regressions were used to determine association between psychological distress and potential explanatory variables. RESULTS A total of 7607 healthcare professionals participated in the study (1760 nurses, 2843 medical practitioners and 3004 other healthcare professionals). Half of the nurses, 41% of medical practitioners and 47% of other healthcare professionals were classified as psychologically distressed. Those who were of older age, provided with well-being support services and having a positive outlook on the healthcare system were significantly less likely to be distressed. Being female medical practitioners and female other healthcare professions, requesting routine counselling, being concerned about not having enough leave and that their life insurance policy did not cover COVID-19 were more likely to be distressed. CONCLUSIONS Psychological well-being of HCWs in South Africa is at risk. We recommend that psychological distress of HCWs be routinely assessed and that routine counselling, well-being support services, appropriate hazardous leave and insurance be provided to all HCWs.Contribution: This study adds to the literature on the psychological distress faced by HCWs in South Africa during COVID-19.