Vaccination is the most cost-effective way of preventing Coronavirus Disease 2019 (COVID-19) although there was a considerable delay in its institution in Tanzania. This study assessed health care workers’ (HCWs) self-perceived infection risk and uptake of COVID-19 vaccines. A concurrent embedded, mixed methods design was utilized to collect data among HCWs in seven Tanzanian regions. Quantitative data was collected using a validated, pre-piloted, interviewer administered questionnaire whereas in-depth interviews (IDIs) and focus group discussions (FGDs) gathered qualitative data. Descriptive analyses were performed while chi-square test and logistic regression were used to test for associations across categories. Thematic analysis was used to analyze the qualitative data. A total of 1,368 HCWs responded to the quantitative tool, 26 participated in the IDIs and 74 in FGDs. About half of the HCW (53.6%) reported to have been vaccinated and three quarters (75.5%) self-perceived to be at a high risk of acquiring COVID-19 infection. High perceived infection risk was associated with increased COVID-19 vaccine uptake (OR 1.535). Participants perceived that the nature of their work and the working environment in the health facilities increased their infection risk. Limited availability and use of personal protective equipment (PPE) was reported to elevate the perceived infection risks. Participants in the oldest age group and from low and mid-level health care facilities had higher proportions with a high-risk perception of acquiring COVID-19 infection. Only about half of the HCWs reported to be vaccinated albeit the majority recounted higher perception of risk to contracting COVID-19 due to their working environment, including limited availability and use of PPE. Efforts to address heightened perceived-risks should include improving the working environment, availability of PPE and continue updating HCWs on the benefits of COVID-19 vaccine to limit their infection risks and consequent transmission to their patients and public.