Background. Ethiopia has one of the lowest HIV prevalence rates in East Africa, but there are still more than one million people estimated to be living with HIV in Ethiopia. This study was aimed at assessing the comprehensive HIV/AIDS knowledge and sexual behavior among university students. Methodology. A cross-sectional comparative study was done with quantitative and qualitative data collection with a stratified sampling technique. The quantitative data were edited, coded, entered, and analyzed using SPSS software version 20. Result. Both comprehensive knowledge of HIV/AIDS transmission and prevention method were higher in the intervention group (75.8% and 48.5%) than comparative group (68.6% and 42.5%) which had a significant difference (P < 0.05). Life time sexual intercourse was higher in the intervention group (40.8%) as compared to the comparative group (34.6%). But sexual condom utilization in the past 12 months was higher in the intervention group (73.2%) as compared to the comparative group (56.9%) which had a significant difference (P < 0.05). Similarly, history of sexual transmitted disease report was higher in the comparative group (6.3%) as compared to the intervention (4.6%). Among sexual experience respondents in the last 12 months, 32% of them in the intervention and 35.5% of them in the comparative group have had multiple sexual partners. Conclusion. The intervention group had higher comprehensive knowledge of HIV/AIDS and condom utilization. But a higher percentage of students were engaged in risky sexual behavior. Therefore, emphasis should be given on designing different strategy to reduce risky sexual behavior and increase comprehensive HIV/AIDS knowledge.