Introduction: Half of all new human papillomavirus (HPV) infections occur in adolescents and young adults, and this population has poor HPV vaccination rates. Rural areas of the U.S. have high rates of HPV-related diseases and low vaccination rates as well. The purpose of this study was to determine the perceived barriers and facilitators to HPV vaccination among adolescents and their caregivers in rural south Alabama. Methods: Vaccinated and non-vaccinated adolescents ages 11–18 years old and primary caregivers were recruited from three rural counties in south Alabama. Participants completed individual interviews to discuss perceived barriers to vaccination and factors influencing their decision to vaccinate. Discussion groups were held to determine potential solutions to barriers elucidated from the interviews. Interview and discussion group transcripts were analyzed, and themes were identified. Results: Approximately 62.5% of adolescents had not initiated the HPV vaccine series. Of those adolescents who started the vaccine series (n = 9, 37.5%), about half completed it (n = 5). Few participants in this study reported speaking with their health care provider (HCP) about the vaccine in the past year. Lack of information about the vaccine, its side effects, and no HCP recommendation were common barriers cited by non-vaccinators. Facilitators to vaccination included cancer prevention, discussion with HCP, and peer testimonials. Potential solutions to barriers were also discussed. Conclusions: Proposed strategies to increase HPV vaccination were similar between vaccinated and non-vaccinated groups. Education about HPV and the HPV vaccine is needed throughout these rural south Alabama communities to ensure informed decisions are made about vaccination and to increase vaccination rates.