Background: substance use is prevalent in Ethiopia. Substance use can have several health problems that are potentially harmful in educational performance, social issues, psychological and physical wellbeing; especially on youth and adolescents. This study aimed to determine the prevalence of lifetime and last one-month substance use and its associated factors among technical and vocational education and training College Students (TVET) in Ataye town. Methods: an institution based cross-sectional study was conducted. Participants were selected by using simple random sampling technique. Chi-square with its p-value was used to identify correlates for each substance use. Bivariate and multivariate binary logistic regression analysis was performed to identify associated factors after controlling cofounding. Odds ratio with their 95% confidence interval, and P < 0.05 was used to declare the significance of associated factors. Results: A total of 483 individuals were participated, which was a response rate of 94%. The prevalence of lifetime substance use was 32.5% (95% CI: 28.2, 36.5). The prevalence of last month's substance use was 21.9% (95% CI= 18.2, 25.5). Among lifetime users, the majority 98(25.5%) were chewed Khat; followed by alcohol drinking 75(19.5%). Cigarettes, cannabis, and cocaine users were 15.3%, 2.5%, and 7.2% respectively. Among last month's substance users, the same proportions (21.9%) chewed Khat; followed by alcohol drinking, (16.6%) and cigarette smoking, (15.3%). Of last month's substance users, 1.2% and 3.3% of students used Cannabis and cocaine respectively. Using multivariate binary logistic regression, Being male (AOR=2.2, 95%CI: 2.3, 3.84), Being from divorced family (AOR=4.1,95%CI: 1.1, 5.8), Living > 20 years in the town (AOR=3.45,95%CI: 1.18,10.1), had family member substance user (AOR=2.5, 95%CI: 1.1, 5.8), had intimate friend substance user (AOR=5.3,95%CI: 2.6,10.9), and availability of substances (AOR=2.3,95%CI: 1.2,4.4.) were independent predictors of lifetime substance use among TVET college students. Conclusions: The prevalence of last month and lifetime substance use among Ataye TVET College students were analogous with other studies done in Ethiopia. Cannabis and cocaine are illegal drugs in Ethiopia. But, the reported proportion of these illegal drug use was significant and needs government attention. Overall, Substance use among adolescents should get further emphasis to lower the prevalence.