Background: The COVID-19 pandemic overwhelmed health facilities and presented healthcare workers (HCWs) with a new infectious disease threat. In addition to a sanitary crisis, Brazil still had to face major political, economic, and social challenges. This study aimed to investigate mental health outcomes in frontline HCWs in different regions of the country and at different epidemic times. We also sought to identify the main risk factors associated with these outcomes. Methods: A cross-sectional online survey using respondent-driven sampling was conducted to recruit physicians (n = 584), nurses (n = 997), and nurse technicians (n = 524) in 4 regions of Brazil (North, Northeast, Southeast, and South) from August 2020 to July 2021. We used standardized instruments to screen for common mental disorders (CMD)(SRQ-20), alcohol misuse (AUDIT-C), depression (PHQ-9), anxiety (GAD-7), and post-traumatic stress disorder (PTSD)(PCL-5). Gile's successive sampling estimator was used to produce weighted estimates. We created a three-cluster data set for each HCW category and developed a hierarchical regression model with three levels: individual characteristics; workplace-related aspects; COVID-19 personal experience. The impact of the epidemic moment on the outcomes was also studied. Results: The prevalence of probable CMD was 26.8-36.9%, alcohol misuse 8.7-13.6%, depression 16.4-21.2%, anxiety 10.8-14.2%, and PTSD 5.9-8.0%. We found a stronger association between mental health outcomes and the following factors: history of psychiatric disorders, female gender, and clinical comorbidities (level 1); work overload and family isolation (level 2); sick leave (level 3). Epidemic variables, such as the number of deaths and trend of deaths by COVID-19, had almost no impact on the outcomes. Conclusion: An alarmingly high prevalence of depression and anxiety was found in Brazilian frontline HCWs. Individual factors were the most strongly associated with mental health outcomes. These findings indicate the need to develop programs that provide emotional support, identify professionals at risk and refer them to specialized treatment when necessary.