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Background: Mental illnesses among children and adolescents are under-recognized and under-treated problems. Depression is one of today's all-too-silent health crises in caregivers. Although primary caregivers of children and adolescents with mental illness are more frequently depressed, little attention is being given to the problem in Ethiopia. Thus, this study aimed to assess prevalence of depression and associated factors among primary caregivers of children and adolescents with mental illness in Ethiopia., Methods: Institution-based cross-sectional study was conducted among primary caregivers of children and adolescents with mental illness in Ethiopia. Systematic random sampling was used to recruit a total of 416 study participants. Patient Health Questionnaire-9 was used to measure depression. After descriptive statistics was conducted, binary logistic regression was employed to carry out bivariate and multivariate analysis., Result: The overall prevalence of depression was 57.6% with 95% CI (53, 62.7). The prevalence of depression among female primary caregivers was 64.6% (n = 181). Female sex (AOR = 2.4, 95% CI: 1.18,4.89), duration of care > 5 years (AOR = 4.2, 95% CI: 2.02,8.70), absence of other caregiver (AOR = 2.7, 95% CI: 1.41,5.34), being mother (AOR = 3.9, 95% CI: 1.90,8.04), autistic spectrum disorder (ASD) (AOR = 4.7, 95% CI: 2.06,10.54) and attention deficit /hyperactivity disorder (ADHD) (AOR = 5.3, 95% CI: 2.14,13.23) diagnosis of children and adolescents and poor social support (AOR = 5.5, 95% CI: 2.04,15.02) were associated with depression., Conclusion: The prevalence of depression among primary caregivers of children and adolescents with mental illness attending treatment in St. Paul's hospital millennium medical college (SPMMC) and Yekatit-12 hospital medical college (Y12HMC) was high. Therefore, it needs to screen and treat depression in primary caregivers of children and adolescents having follow-up at child and adolescent clinics especially for those primary caregivers who are female, mother, gave care for > five years, have no other caregiver, have children diagnosed with ASD and ADHD and have poor social support.