BACKGROUND: A healthy and productive health workforce is central to a well-functioning health system. However, health workers are at high risk of poor psychological wellbeing due to their particularly strenuous work demands. While mental health of health workers is a well-researched issue in high-income countries, research from low- and lower-middle-income countries (LLMIC) has begun to emerge only recently. The review aims to synthesize this body of research, specifically to assess the prevalence of mental health issues among health workers in LLMIC, to identify factors associated with good or poor mental health, and to highlight gaps in knowledge. METHODS: We will perform a systematic search of the published English and French language literature (from inception onwards) in MEDLINE, EMBASE, and PsycINFO. Eligible for inclusion are observational studies (e.g., cross-sectional, case-control, or cohort) and control arms of randomized controlled trials reporting investigations on the nature, prevalence, and factors associated with mental health or psychological wellbeing among formally trained health professionals and health associate professionals delivering health services in formal healthcare facilities in LLMIC. The primary outcomes will be burnout, depression, and general psychological wellbeing. Secondary outcomes include other specific mental health diagnoses, as well as general psychological stress, distress and/or trauma if work-related and explicitly framed as a mental health issue. Two authors will independently examine the studies against the eligibility criteria in the stages of title, abstract, and full-text study selection, as well as assess the risk of bias in included studies using standard checklists depending on study design. Disagreements will be resolved in discussion with the third author. Data will be extracted from included studies using a predefined and piloted coding framework. Given the anticipated heterogeneity of studies, we do not expect to be able to conduct meta-analysis and plan to summarize the extracted data in narrative form. The framework method will be used to organize narrative data by subthemes and explore patterns. DISCUSSION: In assessing the prevalence of mental health issues among healthcare professionals in LLMIC and identifying factors associated with positive or poor mental health, the review aims to synthesize all possible available information for policy makers and health system managers on a potentially highly important but not yet much-discussed issue and to highlight gaps in currently available knowledge. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews PROSPERO (registration number CRD42019140036).