Objectives: Given the effectiveness of human papillomavirus (HPV) vaccination in preventing cervical cancer and other diseases, as well as the low rates of HPV vaccination in the United States, it is important to examine the determinants of perceived HPV vaccine effectiveness. In this study, we examined the associations between potential factors associated with perceived HPV vaccine effectiveness. Methods: We utilized data (N = 718) from the nationally representative 2017 Health Information National Trends Survey (HINTS). We examined the associations of health-related social media use, patient-centered communication, and HPV knowledge with perceived HPV vaccine effectiveness in preventing cervical cancer. We reported descriptive statistics, and conducted bivariable analyses, multivariable analysis, and mediation analyses. Results: Perceived HPV vaccine effectiveness was associated with sex, age, education, health-related social media use, and HPV knowledge. Additionally, HPV knowledge mediated the associations of health-related social media use and patient-centered communication with perceived HPV vaccine effectiveness. Conclusions: Improving health-related information from social media, patient-centered communication, and HPV knowledge may increase perceived HPV vaccine effectiveness and ultimately, vaccine adoption.