This descriptive, observational paper utilizes the comparative case study approach to analyze the application of the HIPE™ Framework to two health campaigns addressing vaccine hesitancy in underserved communities. Exposure to inaccurate/misleading health information impacts vaccination adoption, especially for individuals with low health/digital literacy. Underserved groups—like minority, racial/ethnic, or rural populations—typically have lower literacy and higher rates of vaccine hesitancy. Grounded in persuasion and behavioral change theory, the Health Information Persuasion Exploration (HIPE™) Framework was applied to the Black/Haitian community in Miami-Dade, Florida and the Migrant Agricultural Worker Community in Central Valley, California. The campaigns addressed each community’s unique characteristics via Detect, Analyze, Design, and Evaluate phases of the HIPE framework. Both campaigns achieved their respective vaccine uptake goals. For Miami-Dade, over 850 vaccinations were administered (the goal was 800 vaccinations), and vaccination rates increased by 25.22%. In Central Valley, vaccination rates for 5–11-year-old children in Merced and Stanislaus counties increased about 20% and 14%, respectively, and overall vaccination rates increased compared to surrounding counties. Discussion of the results and recommendations for future research highlight the potential efficacy of applying the HIPE™ Framework for developing health campaigns and response strategies to improve health outcomes.