BackgroundLimited comprehensive knowledge of HIV/AIDS is highlighted as one of the major factors linked to the high prevalence of HIV among adolescents and young girls. Thus, it is crucial to identify factors that facilitate or hinder adolescent girls from having comprehensive knowledge of HIV/AIDS. We, therefore, assessed the prevalence of comprehensive knowledge about HIV/AIDS and associated factors among adolescent girls in Rwanda.MethodsWe used secondary data from the Rwanda Demographic and Health Survey (RDHS) 2020 comprising 3258 adolescent girls (aged 15 to 19 years). Comprehensive knowledge was considered if an adolescent girl answered correctly all the six indicators; always using condoms during sex can reduce the risk of getting HIV, having one sexual partner only who has no other partners can reduce the risk of getting HIV, a healthy-looking person can have HIV, can get HIV from mosquito bites, can get HIV by sharing food with persons who have AIDS, and can get HIV by witchcraft or supernatural means. We, then, conducted multivariable logistic regression to explore the associated factors, using SPSS (version 25).ResultsOf the 3258 adolescent girls, 1746 (53.6%, 95%CI: 52.2–55.6) had comprehensive knowledge about HIV/AIDS. Adolescent girls with secondary education (AOR = 1.40, 95% CI: 1.13–3.20), health insurance (AOR = 1.39, 95% CI: 1.12–1.73), a mobile phone (AOR = 1.26, 95% CI: 1.04–1.52), exposure to television (AOR = 1.23, 95% CI: 1.05–1.44), and a history of an HIV test (AOR = 1.26, 95% CI: 1.07–1.49) had higher odds of comprehensive HIV knowledge, compared to their respective counterparts. However, girls residing in Kigali (AOR = 0.65, 95% CI: 0.49–0.87) and Northern (AOR = 0.75, 95% CI: 0.59–0.95) regions, and those of Anglican religion (AOR = 0.82, 95% CI: 0.68–0.99) had less odds of comprehensive knowledge compared to those in Southern region and of the Catholic religion.ConclusionsTo increase the comprehensive understanding of the disease at a young age, the need for expanded access to HIV preventive education through formal educational curriculum, and mass and social media via mobile phones is highlighted. In addition, the continued involvement of key decision-makers and community actors, such as religious leaders, is vital.