Background. Adolescent anemia is a major public health problem worldwide. Adolescents (10–19 years) are at an increased risk of developing anemia due to increased iron demand during puberty, menstrual losses, limited dietary iron intake, and faulty dietary habits. Objective. To assess the prevalence of anemia and associated factors among male and female adolescent students in Dilla Town, Gedeo Zone, Southern Ethiopia, May 2018. Methods. A school-based comparative cross-sectional study was employed among 742 school adolescents. Basic characteristics, anthropometric measurements, haemoglobin measurement, and others were collected. Data were analyzed using SPSS version 20 software, and descriptive statistics were computed for all variables. Bivariate and multivariable logistic regression analyses using binary logistic regression were done, the results were interpreted by using AOR with their corresponding 95% CI, and statistically significant difference was declared at p<0.05Result. Out of the total 742 respondents, 377 (50.8%) were males and 365 (49.2%) were females. The overall prevalence of anemia was 21.1%, and the prevalence of anemia was 22.5% among male adolescents and 19.7% among females. Male adolescent students within the early adolescence age group (10–13 yrs) (AOR 0.27, 95% CI, 0.08–0.87), those consuming fibre-rich foods daily (AOR 0.11, 95% CI, 0.02–0.61), and those having no intestinal parasites (AOR 0.04, 95% CI, 0.02–0.09) were less likely to be anemic. Similarly, female adolescent students not having intestinal parasites (AOR 0.05, 95% CI, 0.01–0.11) were less likely to develop anemia while those from malaria endemic area (AOR 2.57, 95% CI, 1.13–5.83) were identified to be more anemic. Conclusion. This study identified that anemia was a moderate public health significance in the study area, and the prevalence of anemia was slightly higher among male than female adolescents. Age category, frequency of eating fibre-rich foods, and positive intestinal parasite tests were factors contributing for anemia among male adolescents while presence of intestinal parasite and malaria endemicity were the determinants of anemia among female adolescents.