ObjectiveTo examine the association between YouTube usage and HPV-related cancer knowledge (cervical, anal, oral and penile).Study designCross-sectional study using data from the Health Information National Trends survey conducted between 2017 and 2020 (N= 16,092). Logistic regression was used to analyze the independent effect of YouTube use on cancer knowledge, controlling for sociodemographic characteristics.ResultsRespondents' knowledge of HPV-related cancers varied: 49.9% about cervical, 18% anal, 20.1% oral and 20.4% penile cancers. YouTube use was associated with increased knowledge for all cancers (cervical: OR 2.66, 95% CI 2.04, 3.46; anal: OR 1.83, 95% CI 1.32, 2.53; oral: OR 1.89, 95% CI 1.37, 2.61; penile OR 2.00, 95% CI 1.44, 2.77) in models adjusted for all covariates. Other independent predictors of HPV-related cancer knowledge included female gender, younger age, a higher income, and higher education.Conclusion(s)YouTube could play an important role in educating people about HPV-related cancers and should also target other populations, such as males and those with less formal education.InnovationThe study provides novel insights into the potential of YouTube as an educational tool for promoting cancer knowledge with the goal of cancer prevention.