Abstract Background Depression is a major population health challenge globally. This systematic review and meta-analysis aims to (i) determine depression prevalence and (ii) identify the risk and protective factors of depression among healthcare workers (HCWs) in the Eastern Mediterranean Region (EMR). Methods The protocol was registered on Open Science Framework (registration ID: https://osf.io/rdv27 ). We searched five databases (PubMed, Embase, PsycINFO, Al Manhal, Google Scholar) till July 22, 2020 without language restrictions. We included studies from the EMR using a depression screening or diagnostic instrument to measure the depression prevalence among HCWs. Studies were assessed and data were pooled using random-effects meta-analysis based on the Cochrane handbook. Results The systematic review identified 108 studies from 12 EMR countries with varying quality. Working long hours, poor sleep quality and being female were risk factors for depression in EMR HCWs. The meta-analysis comprised 77 studies providing 122 prevalence measures across 7 EMR countries. The pooled prevalence of depression among EMR HCWs was 33.03% (95% CI = 27.40–39.19%). Emergency HCWs had markedly higher rates of depression [53.14% (95% CI = 26.63–77.99%)] compared to HCWs of other specialties. Most studies had an appropriate sample size. Conclusions Depression among EMR HCWs is a major concern. Steps must be taken to prevent, identify, and manage depression among HCWs. Fostering a compassionate and empathetic environment is critically important to building a resilient healthcare system. Generating high-quality regional data from longitudinal studies on mental health will further contribute to a better understanding and management of depression among EMR HCWs.