This qualitative study explores how religious leaders in Ghana view polio and polio vaccine-related knowledge and perceptions of the community members. It also examines the personal characteristics of those who are most likely to accept or reject the vaccine. On the basis of the findings, this study provides a set of evidence-based recommendations to support religious leaders' efforts to create polio vaccine demand in their communities. The study is based on focus group discussions conducted with religious leaders from various geographic locations across Ghana. The discussions were transcribed verbatim and analyzed thematically. Twenty religious leaders, including Christian, Muslim, and leaders of traditional African religions, participated in the study. The findings show that both religious leaders and community members lack knowledge and have multiple culturally and religiously influenced explanations for polio. In addition, the findings reveal that vaccine safety and efficacy are linked to emotional narratives, and receiving the polio vaccine is not a social norm in all communities. Educated mothers in urban settings were identified as those most receptive to the polio vaccine. To create polio vaccine demand, religious leaders need to combat misinformation and the negative perceptions about the vaccine. Recommendations include conveying high-quality information to community members, developing tactics to address culturally and religiously sensitive matters, using emotionally inspired personal accounts to enhance positive attitudes toward polio vaccines and act as catalysts for positive social norms towards the polio vaccine. Educated mothers from urban areas can be engaged as champions in vaccine demand creation.