Background. The use of substances such as cigarettes, khat, alcohol, and other illicit drugs like hashish, heroine, cannabis, and cocaine is a global major public threat, which affects young adult people particularly in developing countries. This study aims to assess the risk factors associated with substance use and exposure to sexually explicit materials among high-school adolescents in north Shewa zone, Oromia region. Method. A cross-sectional study was conducted to assess substance use and exposure to sexually explicit materials among high-school adolescents in North Shewa zone, Oromiya, Ethiopia, using a structured self-administered questionnaire adapted from the 2008 “Community That Care Youth Survey” for adolescent substance use and problem behaviors. The study used descriptive statistics and logistic regression analysis to identify the significant factors associated with substance use and exposure to sexually explicit materials among high school adolescents in the study area. Result. The prevalence of lifetime and current substance use was 47.7% (95% CI: 0.427, 0.527) and 30.4% (95% CI: 0.258, 0.350), respectively. 17.8% use khat in their life and 16.6% used khat in the past 30 days; 42.2% ever used alcohol and 26.1% currently uses alcohol; 4.8% and 4.5% used cigarette in lifetime and in the past 30 days, while 16.4% use other illicit drugs in lifetime and 8.4% use illicit drugs in the past 30 days, respectively. Distributions of substance use by sex indicate that male adolescents are more like likely 61.1% use substances than females. While, the prevalence of exposure to sexually explicit materials among high school adolescents was 35.8% (95% CI: 0.310, 0.406). Factors positively associated with increased substance use were being male (OR = 2.334, 95% CI: 1.549, 9.926), living through high level of family conflict (OR = 6.25, 95% CI: 1.745, 10.00), poor family management OR = 27.084, 95% CI: 1.624, 45.56), peer pressure (OR = 12.882, 95% CI: 1.882, 88.153), poor academic performance (OR = 14.48, 95% CI: 1.290, 162.58), and low school commitment (OR = 11.951, 95% CI: 1.418, 100.73). While, being male (OR = 7.52, 95% CI: 2.611, 21.739), age 14–16 (OR = 0.201, 95% CI: 0.071, 0.565), friends watch/read sexually explicit materials (OR = 5.376, 95% CI: 1.010, 28.571), and khat chewing (OR = 12.5, 95% CI: 2.924, 25.632) were factors significantly associated with high-school adolescents exposure to sexually explicit materials. Conclusion. The magnitude of prevalence for substance uses and exposure to sexually explicit materials in the study area was still higher. Therefore, interventions that focus on family management, peer pressure, and school commitment are required to decrease the prevalence of substance uses and exposure to sexually explicit materials among high-school adolescents.