Background The human papillomavirus (HPV) vaccine is recommended for adolescents and young adults to prevent HPV-related cancers and genital warts. However, HPV vaccine uptake among the target age groups is suboptimal. Objective The aim of this infodemiology study was to examine public online searches in the United States related to the HPV vaccine from January 2010 to December 2021. Methods Google Trends (GT) was used to explore online searches related to the HPV vaccine from January 1, 2010, to December 31, 2021. Online searches and queries on the HPV vaccine were investigated using relative search volumes (RSVs). Analysis of variance was performed to investigate quarterly differences in HPV vaccine searches in each year from 2010 to 2021. A joinpoint regression was used to identify statistically significant changes over time; the α level was set to .05. Results The year-wise online search volume related to the HPV vaccine increased from 2010 to 2021, often following federal changes related to vaccine administration. Joinpoint regression analysis showed that HPV vaccine searches significantly increased on average by 8.6% (95% CI 5.9%-11.4%) across each year from 2010 to 2021. Moreover, HPV vaccine searches demonstrated a similar pattern across years, with search interest increasing through August nearly every year. At the state level, the highest 12-year mean RSV was observed in California (59.9, SD 14.3) and the lowest was observed in Wyoming (17.4, SD 8.5) during the period of 2010-2021. Conclusions Online searches related to the HPV vaccine increased by an average of 8.6% across each year from 2010 to 2021, with noticeable spikes corresponding to key changes in vaccine recommendations. We identified patterns across years and differences at the state level in the online search interest related to the HPV vaccine. Public health organizations can use GT as a tool to characterize the public interest in and promote the HPV vaccine in the United States.