The COVID-19 pandemic disrupted healthcare delivery within safety-net settings. Barriers to and facilitators of human papillomavirus (HPV) vaccination during the pandemic can inform future HPV vaccine strategies for underserved communities. Qualitative interviews (n = 52) between December 2020 and January 2022 in Los Angeles and New Jersey were conducted with providers, clinic leaders, clinic staff, advocates, payers, and policy-level representatives involved in the HPV vaccine process. Using the updated Consolidated Framework for Implementation Research we identified (1) outer setting barriers (i.e., vaccine hesitancy driven by social media, political views during the pandemic) and facilitators (e.g., partnerships); (2) inner setting clinic facilitators (i.e., motivation-driven clinic metrics, patient outreach, vaccine outreach events); (3) individual characteristics such as patient barriers (i.e., less likely to utilize clinic services during the pandemic and therefore, additional outreach to address missed vaccine doses are needed); (4) innovations in HPV vaccination strategies (i.e., clinic workflow changes to minimize exposure to COVID-19, leveraging new community partnerships (e.g., with local schools)); and (5) implementation strategies (i.e., multisectoral commitment to HPV goals). Pandemic setbacks forced safety-net settings to develop new vaccine approaches and partnerships that may translate to new implementation strategies for HPV vaccination within local contexts and communities.