Background: Substance use remains high among Ethiopian youth and young adolescents particularly in high schools and colleges. The use of substance by college and university students of Ethiopia is current health problem. However, the magnitude of substance use and the factors associated with it has not been investigated among college students in the Afar region. Methodology: A cross sectional study was conducted to determine the overall prevalence of substance abuse among students and factors associated with it. Simple random sampling technique was used to select 479 students from all batches after stratifying them based on year of study. A pretest semi structured anonymous questionnaire was used to collect data. The data was analyzed using Epi-Data latest version and SPSS version 20 statistical package. The prevalence and predictors of substance abuse was examined by descriptive statistics and logistic regression with significance level set at p < 0.05. Multivariate logistic regression analyses were also used to assess the magnitude of associations between substance use and socio-demographic and behavioral correlates. Finally, substance abuse was measured by using CAGE-AID. Result and conclusion: About 61.8% of respondents replied that they have tried any substance from which 77.5% is covered by alcohol abuse followed by khat chewing (26.1%). Additionally, majority of the respondent (45%) said they began use of substance at secondary school level to get personal pleasure in hot weather (47%) followed by due to peer pressure (45%). It was associated positively with certain variables such as male participants, urban setting, and availability of drugs. This result implied a significant proportion of student abuse substances. Keywords: substance use, khat; alcohol; tobacco; college students