The human papillomavirus (HPV) vaccine is relatively novel to people in China. Social media is becoming an important channel for learning new health information. However, limited is known about what HPV vaccine information has been disseminated on social media, and how such online information is associated with health-related behaviors in China. Based on Longo et al.’s model of patient use of healthcare information for healthcare decision, and Longo’s model of health information seeking behaviors, this study examined HPV vaccine-related information type and information acquisition pattern. Following the mixed-methods approach, we first crawled 67,773 postings about HPV vaccine on Weibo, the largest microblogging website in China, and performed topic modeling to identify HPV vaccine-related topics that are prevalent on Weibo. The results showed six major topics about HPV vaccine, namely policy, guidance information, advertising, scandals, personal experience sharing, and HPV risks. Second, we conducted an online survey (n = 1,982) to investigate how scanning, seeking, and discussing the six HPV vaccine topics identified from big data analytics can affect HPV vaccine knowledge, safety concern, and vaccination intention. We documented significant impacts of social media health communication on users’ health knowledge, attitude and behavioral intention.