Abstract Background Women of reproductive age in sub-Saharan African (SSA) share the greatest burden of the HIV/AIDS epidemic. Comprehensive knowledge about HIV is seen as pivotal in combating the epidemic. Therefore, this study aimed to assess comprehensive knowledge about HIV/AIDS and associated factors among women of reproductive age in sub-Saharan Africa. Objective To examine comprehensive knowledge about HIV/AIDS and associated factors among women of reproductive age in sub-Saharan Africa. Methods We used the most recent SSA countries Demographic and Health Surveys (DHS) data. To assess comprehensive knowledge, a composite score of six separate questions (can get HIV by witchcraft or supernatural means, can reduce risk of getting HIV by using condoms during sex, reduce the risk of getting HIV by having one sex partner only, can get HIV from mosquito bites, can get HIV by sharing food with a person who has HIV/AIDS, and a healthy-looking person can have HIV) was used. Those who answered all six questions correctly were considered to have comprehensive knowledge. To assess the factors associated with comprehensive knowledge of HIV/AIDS, we used a multilevel binary logistic regression model since the data had hierarchical nature. Results In this study, the comprehensive knowledge about HIV/AIDS was 38.56% (95% CI: 38.32, 38.75). Both individual and community-level factors were associated with comprehensive knowledge about HIV/AIDS. Among individual-level factors, older age, having primary and above educational level, being from wealthy households, contraceptive use, listening to the radio, and reading newspaper were associated with higher odds of comprehensive knowledge about HIV/AIDS. Being from urban areas and the Eastern African region were the community-level factors that were associated with higher odds of comprehensive knowledge about HIV/AIDS. Conclusion The study found that comprehensive knowledge of HIV/AIDS is low. Individual and community-level factors were associated with comprehensive knowledge of HIV/AIDS. Therefore, giving special attention to those young women, women who had no formal education, those from poor socioeconomic status, and those who are from remote areas could decrease the epidemics of HIV/AIDS by increasing the comprehensive knowledge about HIV/AIDS. Besides, it is better to strengthen media campaigns regarding HIV/AIDS to increase comprehensive knowledge about HIV/AIDS.