The study examined whether the 3R (reframe, prioritize, and reform) communication model intervention can impact parents’ and adolescents’ HPV vaccination acceptability. We used face-to-face methods to recruit participants from three local churches in the Ashanti Region of Ghana. Participants completed pre- and post-intervention assessments based on the validated Theory of Planned Behavior survey. We organized two face-to-face presentations for parents and adolescents separately for parents (n = 85) and adolescents (n = 85). Participants’ post-intervention vs. pre-intervention scores for attitude (mean = 35.46 ± SD = 5.46 vs. mean = 23.42 ± SD = 8.63), knowledge (M = 28.48 ± SD = 5.14 vs. M = 16.56 ± SD = 7.19), confidence (M = 8.96 ± SD = 3.43 vs. M = 6.17 ± SD = 2.84), and intention for vaccine acceptance (M = 4.73 ± SD = 1.78 vs. M = 3.29 ± SD = 1.87) increased significantly (p < 0.001). The intervention showed that for every one-unit increase in the participants’ self-confidence and attitude scores, the odds of the HPV vaccination acceptability increased by 22% (95% CI: 10–36) and 6% (95% CI: 0.1–12), respectively. Intention for vaccine acceptance, F (1167) = 6.89, and attitude toward vaccination, F (1167) = 19.87, were significantly higher among parents than adolescents (p < 0.001), after controlling for the baseline scores. These findings suggest that the intervention targeting parents’ and adolescents’ attitudes and knowledge has the potential to increase HPV vaccination acceptance in Ghana.