The objective of this study was to assess depressive symptoms among rural health workers (RHWs) through a multi-factorial socio-ecological framework (SEF) encompassing personal, interpersonal, organizational and community components. Patients and Methods: A random sample of 394 RHWs in all rural areas of East Azerbaijan and fulfilling our other inclusion criteria were recruited. The participants underwent the Short-Form Beck's Depression Inventory and a validated researcher-constructed SEF questionnaire, including subscales on personal, interpersonal, organizational and community factors associated with depressive symptoms. Internal consistency and factor structure parameters of the SEF were also calculated. Results: A total of 394 RHWs were screened, of whom 170 (43.2%) had mild to major depressive symptoms. Only 6.8% were identified with major depressive symptoms. The SEFbased scale was found to have acceptable content validity (content validity index and ratio were 0.80 and 0.77, respectively) and reliability (Cronbach's alpha=0.7). In the structural equation modeling, the fit indices showed our model to fit the data well (χ 2 =14.06, df=14, χ 2 / df=1.00, CFI=0.967, RMSEA=0.032). The highest direct contribution to depressive symptoms was found from the personal factors component (β=−2.32). Also, "work load and roles interference" (from organizational level, β=−0.76) and "family/colleague support" (from community level, β=−1.28) made significant direct contributions towards depressive symptoms. Besides the SEF components, female gender (β=1.69), family history of mental illness (β=−1.48), having chronic illnesses (β=−1.64) and being religious (β=3.43) were the strongest direct contributors to depressive symptoms. Conclusion: Depressive symptoms were common among RHWs, arising from all personal-, interpersonal-, organizational-and community-level factors. Our SEF had adequate internal consistency and factor structure parameters to be applied in the Middle East and North Africa (MENA) region countries, such as Iran, as a theoretical framework to plan for interventional efforts aiming at preventing depressive symptoms among RHWs. The burden of depressive symptoms should be reduced through multi-factorial interventions and rational perspectives.