Adolescent COVID-19 vaccination has stalled at 53% in the United States. Vaccinating adolescents remains critical to preventing the continued transmission of COVID-19, the emergence of variants, and rare but serious disease in children, and it is the best preventive measure available to return to in-person schooling. We investigated parent–adolescent COVID-19 vaccine decision-making. Between 24 February and 15 March 2021, we conducted surveys and 12 focus groups with 46 parent–adolescent dyads in Southern California. Parents and adolescents completed a survey prior to participation in a focus group discussion, which focused on exploring COVID-19 vaccine acceptance or uncertainty and was guided by the 5C vaccine hesitancy model. Parents uncertain about vaccinating adolescents expressed low vaccine confidence and high COVID-19 disease risk complacency. Parents who accepted COVID-19 vaccination for adolescents expressed high confidence in health authority vaccine recommendations, high perceived COVID-19 risk, and collective responsibility to vaccinate children. Additionally, unique pandemic-related factors of vaccine acceptance included vaccinating for emotional health, resuming social activities, and vaccine mandates. Among parents, 46% were willing to vaccinate their adolescent, 11% were not, and 43% were unsure. Among adolescents, 63% were willing to vaccinate. Despite vaccine availability, 47% of adolescents remain unvaccinated against COVID-19. Factors associated with vaccine uncertainty and acceptability inform health care practitioner, school, community, and public health messaging to reach parents and adolescents.