HPV vaccination rates remain below target levels among adolescents in the United States, which is particularly concerning in safety-net populations with persistent disparities in HPV-associated cancer burden. Perspectives on evidence-based strategies (EBS) for HPV vaccination among key implementation participants, internal and external to clinics, can provide a better understanding of why these disparities persist. We conducted virtual interviews and focus groups, guided by the Practice Change Model, with clinic members (providers, clinic leaders, and clinic staff) and community members (advocates, parents, policy-level, and payers) in Los Angeles and New Jersey to understand common and divergent perspectives on and experiences with HPV vaccination in safety-net primary care settings. Fifty-eight interviews and seven focus groups were conducted (n = 65 total). Clinic members (clinic leaders n = 7, providers n = 12, and clinic staff n = 6) revealed conflicting HPV vaccine messaging, lack of shared motivation to reduce missed opportunities and improve workflows, and non-operability between clinic electronic health records and state immunization registries created barriers for implementing effective strategies. Community members (advocates n = 8, policy n = 11, payers n = 8, and parents n = 13) described lack of HPV vaccine prioritization among payers, a reliance on advocates to lead national agenda setting and facilitate local implementation, and opportunities to support and engage schools in HPV vaccine messaging and adolescents in HPV vaccine decision-making. Participants indicated the COVID-19 pandemic complicated prioritization of HPV vaccination but also created opportunities for change. These findings highlight design and selection criteria for identifying and implementing EBS (changing the intervention itself, or practice-level resources versus external motivators) that bring internal and external clinic partners together for targeted approaches that account for local needs in improving HPV vaccine uptake within safety-net settings.