Abstract Background Human papillomavirus (HPV) vaccination rates among adolescents are increasing in Minnesota (MN) but remain below the Healthy People 2020 goal of 80% completion of the series. The goal of this study was to identify messaging and interventions impacting HPV vaccine uptake in MN through interviews with clinicians and key stakeholders. Methods We conducted semi-structured key participant interviews with providers and stakeholders involved in HPV vaccination efforts in MN between 2018 and 2019. Provider interview questions focused on messaging around the HPV vaccine and clinic-based strategies to impact HPV vaccine uptake. Stakeholder interview questions focused on barriers and facilitators at the organizational or state level, as well as initiatives and collaborations to increase HPV vaccination. Responses to interviews were recorded and transcribed. Thematic content analysis was used to identify themes from interviews. Results 14 clinicians and 13 stakeholders were interviewed. Identified themes were grouped into 2 major categories that dealt with messaging around the HPV vaccine, direct patient–clinician interactions and external messaging, and a third thematic category involving healthcare system-related factors and interventions. The messaging strategy identified as most useful was promoting the HPV vaccine for cancer prevention. The need for stakeholders to prioritize HPV vaccination uptake was identified as a key factor to increasing HPV vaccination rates. Multiple providers and stakeholders identified misinformation spread through social media as a barrier to HPV vaccine uptake. Conclusion Emphasizing the HPV vaccine’s cancer prevention benefits and prioritizing it among healthcare stakeholders were the most consistently cited strategies for promoting HPV vaccine uptake. Methods to combat the negative influence of misinformation about HPV vaccines in social media are an urgent priority.