This research investigates psychoactive substance abuse that causes significant health problems in its various chemical effects. It also determines the patterns of its use and level of risk of harm assessment to humans. Harmful determination is dependent upon patterns used in psychoactive substance and its associated level of risk among high school students in Afar region, Ethiopia. The study described a survey of 400 high school students in Afar region, with the adoption of Multistage sampling technique on student's selection. Data collected from Jan-Feb/2017 using an instrument called Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), showed 400 students whose responses were 100% effective. Among the study participants, majority of them 231 (60.5%) were males. The result of the study revealed a dependent use pattern with 36.4% for Khat, 14.1% for tobacco products and 4.7% for alcohol beverages, which indicated high risk of problems related to psychoactive substances used requires more intensive treatment. The result also indicated that there is 31.4% harmful used pattern for alcohol beverages followed by khat (13.1%) and tobacco products (9.4%) which was associated with moderate risk of harm from their addiction. The result of independent t-test showed that there was a significant mean difference in alcoholic beverages abuse between male and female students, while no significant mean difference was observed in abuse of khat and tobacco products between male and female students. Relatively, ANOVA result revealed that religion of the respondents had a significant effect on abuse of alcoholic beverages, while no significant mean differences were observed in abusing psychoactive substance like tobacco products and khat across participants upon religion. Generally, the present study revealed a greater percentage of students whose daily dosage of harmful psychoactive substances instigated high and moderate risks. The outcome of this study is there is an urgent need for Government intervention to curtail the menace of harmful psychoactive substances and many other toxicants circulating in the society which are detrimental to health, social, financial, legal and peaceful relationship.