BACKGROUND: Khat use is a well-established public health problem in Yemen, Arabian Peninsula, and Ethiopia. Along with its large scale production, the magnitude of khat use is increasing among students. OBJECTIVE: This study was intended to assess the prevalence, determinants, and effect of khat use on academic performance of high school students in Sidama Ethiopia. METHODOLOGY: A cross-sectional study was conducted from April to June 2015. We used a stratified sampling technique to draw a total of 1,577 students. The data was collected using self-administered questionnaires and analyzed using SPSS version 20. Descriptive statistics and logistic regression models were used to determine the prevalence, effects, and predictors of khat use. RESULT: The life time and current prevalence of khat use were 14.6% and 13%, respectively. Smoking cigarette (AOR=5.1, 95% C.I: 2.3-14.3), drinking alcohol (AOR=3.0, 95% C.I: 1.4-6.3), having a family growing khat (AOR=2.0, 95% C.I: 1.1-2.5), having friend chewing khat (AOR=3. 95% C.I: 2.0-4.6), were some of factors that increased the odds of students' khat use. Student's khat use increased the odds of student's poor academic performance (AOR=2.1, 95% C.I: 1.1-3.9). CONCLUSION: The prevalence of khat use in high khat producing districts of Sidama and its contribution to poor academic performance demand prompt intervention.