Background Preliminary country-specific reports suggest that the COVID-19 pandemic has a negative impact on the mental health of the healthcare workforce. In this paper, we summarize the protocol of the COVID-19 HEalth caRe wOrkErS (HEROES) study, an ongoing, global initiative, aimed to describe and track longitudinal trajectories of mental health symptoms and disorders among health care workers at different phases of the pandemic across a wide range of countries in Latin America, Europe, Africa, Middle-East, and Asia. Methods Participants from various settings, including primary care clinics, hospitals, nursing homes, and mental health facilities, are being enrolled. In 26 countries, we are using a similar study design with harmonized measures to capture data on COVID-19 related exposures and variables of interest during two years of follow-up. Exposures include potential stressors related to working in healthcare during the COVID-19 pandemic, as well as sociodemographic and clinical factors. Primary outcomes of interest include mental health variables such as psychological distress, depressive symptoms, and posttraumatic stress disorders. Other domains of interest include potentially mediating or moderating influences such as workplace conditions, trust in the government, and the country's income level. Results As of August 2021, ~ 34,000 health workers have been recruited. A general characterization of the recruited samples by sociodemographic and workplace variables is presented. Most participating countries have identified several health facilities where they can identify denominators and attain acceptable response rates. Of the 26 countries, 22 are collecting data and 2 plan to start shortly. Conclusions This is one of the most extensive global studies on the mental health of healthcare workers during the COVID-19 pandemic, including a variety of countries with diverse economic realities and different levels of severity of pandemic and management. Moreover, unlike most previous studies, we included workers (clinical and non-clinical staff) in a wide range of settings.