Inadequate adherence to treatment is among the main underlying causes of depression becoming a chronic problem. In developing countries due to limited access to health care, inaccurate diagnoses, and scarcity of medications, poor adherence may become an even larger obstacle in the treatment of depression. The current study aims to assess the magnitude and factors related to treatment non-adherence among patients with depressive disorders. To assess the magnitude and factors associated with treatment non adherence among patients with depressive disorders at St. Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia, 2019. A hospital-based cross-sectional study was conducted among 415 respondents using systematic random sampling technique. Medication adherence was assessed by using Medication Adherence Rating Scale. Data was entered to Epi-data version 3.1 and analyzed using SPSS version 20. Binary logistic analysis was done and P-values less than 0.05 were considered statistically significant. The prevalence of treatment non-adherence among patients with depressive disorders was 26% (95%CI; 21.2, 32.5). Previous suicide attempt (AOR = 3.05, 95%CI; 1.82, 5.12), medication side effects (AOR = 2.46, 95%CI; 1.47, 4.11), moderate to high self-stigma (AOR = 2.60, 95%CI; 1.45, 4.66), and poor quality of life (AOR = 2.47, 95%CI; 1.42, 4.28) were significantly associated with treatment non-adherence among patients with depressive disorders. Treatment non-adherence is a common problem among patients being treated for depressive disorders. Previous suicide attempts, medication side effects, moderate to high self-stigma, and poor quality of life were significantly associated with treatment non-adherence. Appropriate interventions should be developed to promote measures to facilitate adherence in this group of patients, and address the associated factors when applicable.