Up to 80% of adults with attention deficit hyperactivity disorder (ADHD) may have a concomitant psychiatric disorder. ADHD and depression, combined with the demands of University life, can pose serious challenges for students. However, there are limited studies conducted on this topic in our country. Therefore, the current study assessed the magnitude, relationship, and determinants of ADHD and depressive symptoms among students at the University of Gondar. An institution-based cross-sectional study was employed among 1514 undergraduate students at the University of Gondar from June 1-20, 2022. A stratified, simple random sampling technique was applied. Structural equation modeling was employed. The degree of relationship was interpreted based on the adjusted regression coefficient with 95% confidence interval (CI) and p-value (<0.05). In our study, 37.6% [CI: 35.2-40.1%] and 20.01% [CI: 18.1-22.1%] of the participants had depressive and ADHD symptoms, respectively. Chronic illness [β = 0.19, CI; 0.09, 0.30], alcohol use [β = 0.10, CI; 0.03, 0.17], social support [β = -0.23, CI; -0.29, -0.17], problematic internet use (PIU) [β = 0.23, CI; 0.18, 0.27], and insomnia [β = 0.24, CI; 0.17, 0.30] had a direct relationship with depressive symptoms. Mother education level [β = -0.09, CI; -0.13, -0.06], birth order [β = -0.09, CI; -0.11, -0.07], chat chewing [β = 0.18, CI; 0.06, 0.30], and depressive symptoms [β = 0.73, CI; 0.62, 0.86] had a direct relationship with ADHD. Chronic illness [β = 0.14, CI; 0.06, 0.22], PIU [β = 0.16, CI; 0.13, 0.21], social support [β = -0.16, CI; -0.22, -0.12], and insomnia [β = 0.17, CI; 0.13, 0.23] had an indirect effect on ADHD. The prevalence of ADHD and depressive symptoms was high. Chronic disease, alcohol use, social support, PIU, and insomnia had a direct effect on depressive symptoms and an indirect effect on ADHD. Mother education, birth order, chat chewing, and depressive symptoms had a direct effect on ADHD. Our study provided useful clues for clinical treatment and school-based interventions that aim to improve college students' mental well-being. It is better to design school-based intervention and prevention programs to achieve timely diagnosis and treatment of these disorders among university students.