Although there has been an increase focus on recruitment of minority populations at safety-net hospitals into cancer clinical trials, there is still a paucity of research exploring minority participation in cancer clinical trials at safety-net settings. The study utilized a multi-level, qualitative approach to assess the clinical and non-clinical facilitators and barriers to African American participation in cancer clinical trials at a safety-net hospital. From June 2018 to July 2019, cancer survivors (n = 25) were recruited from a cancer center at a safety-net hospital in the southeastern USA and participated in a 60-min focus group. Data was coded and analyzed to identify the most prominent themes. Most participants were female (78%), with a mean age of 56 years. The majority were diagnosed with breast cancer (68%) and disabled or unemployed (55%). Major themes identified were (1) lack of understanding of cancer clinical trials, (2) perceptions and fears of cancer clinical trials, and (3) preferred role and characteristics of patient navigator. The barriers and facilitators to enrollment in cancer clinical trials were more pronounced in the safety-net setting, given the overdue burden of social determinants of health. Study findings yield important insights and essential practices for recruiting and engaging underrepresented Black cancer patients into cancer clinical trials, specifically for safety-net settings. Including patient navigators may help traverse potential barriers to cancer clinical trial participation and will allow for the attention to social determinants of health, and ultimately increase the number of African Americans participating in cancer clinical trials.