Background Youth in general and young females, in particular, remain at the center of HIV/AIDS epidemic. To avoid and prevent HIV infection, comprehensive knowledge as well as correct understanding of transmission and prevention strategies are crucial. Thus, the aim of this study is to explore the predictors of comprehensive knowledge on HIV/AIDS and accepting attitude towards PLWHIV. Methods A cross-sectional study was conducted using data from the 2016 Uganda Demographic Health Survey. A two-stage probability sampling method was applied and data were collected using a standard questionnaire. Of the total 8674 women aged 15–49 years, 1971 eligible women aged 15–24 years were included in this analysis. Data analysis was done using SPSS version 23. A Chi-square test followed by logistic regression analysis was used to explore the relationship between specific explanatory variables and outcome variables. The results were reported using odds ratios with 95% confidence interval. P value less than 0.05 was considered as statistically significant. Results Overall, 99.3% of the unmarried women aged 15–24 years were aware of HIV/AIDS, but only 51.9% had comprehensive knowledge on HIV/AIDS. Around 70% of the respondents were aware that "using condoms every time when having sex" and "having only one faithful uninfected partner" can prevent HIV transmission. About 68% of the unmarried women rejected at least two common local misconceptions about HIV/AIDS. An alarmingly small (20.6%) proportion of the respondents had a positive acceptance attitude towards PLWHIV. All variables were significantly associated with having comprehensive knowledge on HIV/AIDS in the unadjusted logistic regression analysis. After adjustment, older age (20–24 years), being educated, wealthier, and ever been tested for HIV/AIDS became predictors of adequate comprehensive HIV/AIDS knowledge. Moreover, respondents with adequate comprehensive knowledge of HIV/AIDS were more likely (OR 1.64, 95% CI 1.30–2.08) to have a positive acceptance attitude towards PLWHIV than their counterparts. Conclusion Our study demonstrated a remarkably high level of awareness about HIV/AIDS among study participants, but the knowledge and positive acceptance attitude towards PLWHIV were not encouraging. Thus, endeavors to expand and strengthen educational campaigns on HIV/AIDS in communities, health facilities, and schools are highly recommended. Attention should particularly focus on young-aged and disadvantaged women with low educational level, poor socioeconomic status and those who have never been tested for HIV/AIDS.