Nigeria has high rates of sickle cell disease (SCD), which is attributed to the lack of awareness of the disease among the reproductive age in the country. The purpose of this cross-sectional study was to explore the role of religious leaders in contributing to awareness and prevention of SCD in Nigeria. Religious leaders' knowledge, attitude, and prevention and awareness practices of SCD, and how they translated to the prevention of SCD through improved counseling of premarital couples, were explored. A stratified random sampling was employed in selecting a sample of 150 religious leaders from different religious affiliations. Data were collected through a survey of sampled religious leaders in Nigeria by use of semi-structured questionnaires. Correlation analysis was used to determine the relationship among the variables under study. According to study findings, the level of knowledge towards SCD among the religious leaders was high. Additionally, there was no significant relationship between the religious leaders' knowledge of SCD and their efforts in increasing testing and genetic counseling among their congregation members. The level of awareness among the religious leaders did not contribute to the prevention of SCD in the country. The implications for positive social change from this research include religious leaders' commitment to emphasizing genotype testing during regular premarital counseling sessions and including religious leaders in health promotion activities, especially SCD prevention.