BACKGROUND: Adolescents living in war-affected areas are more likely to suffer from depression than adolescents living outside war-affected areas. However, there is limited evidence from Northern Ethiopia that was affected by armed conflicts. This study was conducted to assess the magnitude of depression and to identify inter-related factors with depression and academic performance in armed conflict-affected areas of North Wollo Zone, Ethiopia. METHODS: A school-based cross-sectional study was conducted among high school students in North Wollo Zone, Ethiopia. A multistage sampling method was used, and the study participants were selected using simple random sampling. The Structural Equation Model was used to verify the hypothesized relationship between various internal and external or mediating factors. The effect size was provided using standardized beta coefficients, 95% CI, and statistical significance defined as a p-value <.05. RESULTS: Out of 3,400 study participants, 48.1% (95% CI [46.5%, 49.8%]) endorsed depressive symptoms. Being female (β = .05, 95% CI [0.011, 0.087]), far from family because of education (β = .10, 95% CI [0.060, 0.134]), anxiety (β = .95, 95% CI [0.893, 1.011]), and alcohol use (β = .14, 95% CI [0.108, 0.180]) had a significant and positive association with a total direct effect on depression. Conversely, academic performance (β = -.04, 95% CI [-0.061, -0.011]) had a significant and negative association with a total direct effect on depression. CONCLUSION: This study found a much higher magnitude of depression among students in conflict-affected areas compared to non-affected areas. High school students, particularly girls in conflict-affected areas, need social support and special protection. Additional efforts are needed to ensure safety and security in high schools and establish student support systems such as student counseling and guidance services.