Background Clinical trials are the gold standard for generating evidence on the safety and efficacy of potential new treatments. Yet, Black patients are historically underrepresented in clinical trials for the diseases that disproportionately affect this group. The lack of inclusivity in clinical trials impacts the generalizability of findings and contributes to disparities in health outcomes. To better understand the factors contributing to African American enrollment in trials, we conducted a survey to evaluate the factors contributing to African American’s willingness to participate in clinical trials. The purpose of the study was to identify barriers and facilitators to African Americans' willingness to participate in clinical trials and develop culturally sensitive strategies to enhance the enrollment of diverse patient populations in clinical trials. Methods We created a web-based survey consisting of 38 questions subdivided into three sections: (1) cultural affinity, (2) trust, and (3) background information. The survey was administered via Jotform, a HIPAA-compliant web application. Our target population was Black Americans in the Southern U.S. Participants were recruited using a combination of community-based recruitment and traditional recruitment methods, such as social media and radio advertisements. Results 260 Black adults completed the survey. The most commonly reported barriers to participation included the history of medical research on African Americans, concerns about potential side effects of an experimental treatment, and the absence of Black clinicians involved in research. Facilitators to research participation included greater representation of African Americans in medical research, physician recommendation, IRBs with African American members, thorough explanations about the study, and relevance of the study to the black community. Other notable findings include that only 27.6% and 37.5% of respondents indicated that free transportation to and from the research sites and being paid for participation would make them more willing to participate in clinical research. Conclusion Our findings indicate that Black Americans are open to participating in clinical research. However, culturally sensitive trust and safety measures should be implemented to address the negative effects of a history of abuse, dishonesty, and lack of Black leadership in medicine on people of color’s ability to trust medical research. Plain language study material and explanations, diverse representation in leadership, and active community engagement in the study process are vital steps toward increasing African American research participation.