There is emerging evidence of a rise in new human immunodeficiency virus (HIV) infections in Ethiopia. This may partly be explained by an increase in risky sexual behaviors among high school adolescents. The current study was conducted to explore the association between a set of predictor variables (comprehensive HIV knowledge and condom use self-efficacy score) and an outcome variable of risky sexual behavior among high school adolescents in the Angacha District of Southern Ethiopia. The study employed a quantitative cross-sectional design to answer the research question. Primary data were collected using a self-administered questionnaire from 374 participants using a stratified random sampling technique. Descriptive statistics and bivariate and multivariate logistic regressions were computed using SPSS Version 25. The prevalence of risky sexual behavior among school adolescents was 30.04/per 1000. The Cronbach’s Alpha for condom use self-efficacy score (CUSES) was 0.79. The association between HIV comprehensive knowledge and risky sexual behavior was not statistically significant. A statistically significant association was found between CUSES and the risky sexual behavior of the student, P = 0.048, OR =2.23, 95% CI [1.007, 4.925] when the covariates were held constant. The mean CUSES for males (M = 3.44) was significantly higher than females (M = 3.22), U = 14523.5, P = 0.025, η2 = 0.016). Policy decisions to revitalize school-based adolescent sexual health promotion to empower adolescents with life skills are needed to sustain the gains of HIV/AIDS control and enhance social change in the country.