The result of this study shows that the last twelve month prevalence of khat chewing, shisha smokes, cigarette smoking, alcohol drinking and use other drugs were 10.4%, 5.5%, 7.8%, 37.8% and 3.0% respectively. The cumulative prevalence of substance use for last twelve month (use of one type of substance at least once) was 41.56%. The results also shows that perceived parental monitoring (AOR= 0.63; 95% CI; 0.47, 0.84) and perceived parental injunctive norm (AOR= 0.34 95% CI; 0.14, 0.84) were strong anti-substance use factors. Perceived parental permissiveness (AOR= 1.33; 95% CI; 1.01, 1.75) and family use of substance (AOR= 2.11; 95% CI; 1.55, 2.89) also showed positive association with substance use. Therefore, providing advice, counseling, support, and modeling of behavior and monitoring of children's activities and relationships is effective in reducing students’ attitude towards substance use.