The ability of a health system to withstand shocks such as a pandemic depends largely on the availability and preparedness of health-care workers (HCWs), who are at the frontline of disease management and prevention. Despite the heavy burden placed on HCWs during the COVID-19 pandemic, little is known regarding their experiences in low-income countries. We conducted a web-based survey with HCWs in randomly selected districts of Tanzania to explore their experiences with COVID-19-related prevention and control measures. The survey assessed implementation of COVID-19 control guidelines in health facilities, HCW perceptions of safety, well-being and ability to provide COVID-19 care, and challenges faced by frontline workers during the pandemic. We used multivariate regression analysis to examine the association between HCW and health facility characteristics, a score of guideline implementation, and challenges faced by HCWs. 6,884 Tanzanian HCWs participated in the survey between December 2021 to March 2022. The majority of respondents were aware of the COVID-19 guidelines and reported implementing preventive measures, including masking of both HCWs and patients. However, HCWs faced several challenges during the pandemic, including increased stress, concerns about infection, and inadequate personal protective equipment. In particular, female HCWs were more likely to report exhaustion from wearing protective equipment and emotional distress, while physicians were more likely to experience all challenges. While most HCWs reported feeling supported by facility management, they also reported that their concerns about COVID-19 treatment were not fully addressed. Notably, perceptions of protection and well-being varied widely among different HCW cadres, highlighting the need for targeted interventions based on level of exposure. In addition, various factors such as HCW cadre, facility ownership and COVID-19 designation status influenced HCWs’ opinions about the health system’s response to COVID-19. These findings highlight the importance of consistent implementation of guidelines and social and emotional support for HCWs.