Background The vaccination uptake rates of the human papillomavirus (HPV) vaccine remain low despite the fact that the effectiveness of HPV vaccines has been established for more than a decade. Vaccine hesitancy is in part due to false information about HPV vaccines on social media. Combating false HPV vaccine information is a reasonable step to addressing vaccine hesitancy. Objective Given the substantial harm of false HPV vaccine information, there is an urgent need to identify false social media messages before it goes viral. The goal of the study is to develop a systematic and generalizable approach to identifying false HPV vaccine information on social media. Methods This study used machine learning and natural language processing to develop a series of classification models and causality mining methods to identify and examine true and false HPV vaccine–related information on Twitter. Results We found that the convolutional neural network model outperformed all other models in identifying tweets containing false HPV vaccine–related information (F score=91.95). We also developed completely unsupervised causality mining models to identify HPV vaccine candidate effects for capturing risk perceptions of HPV vaccines. Furthermore, we found that false information contained mostly loss-framed messages focusing on the potential risk of vaccines covering a variety of topics using more diverse vocabulary, while true information contained both gain- and loss-framed messages focusing on the effectiveness of vaccines covering fewer topics using relatively limited vocabulary. Conclusions Our research demonstrated the feasibility and effectiveness of using predictive models to identify false HPV vaccine information and its risk perceptions on social media.