Mindfulness is a promising health promotion strategy for African Americans, and it is imperative that culturally responsive mindfulness approaches be accessible to this population. One way to address this need is to develop and test if culturally responsive mobile health (mhealth) applications are efficacious in reducing stress-related outcomes in this population. With this goal in mind, we employed a repeated-measures randomized control trial (RCT) across a 12-week intervention period to evaluate if participants in the intervention group outperformed a wait-list control group in reductions in stress, depressive symptoms, anxiety, emotional regulation difficulties as well as in increases in self-compassion, resilience, and mindfulness attitudes and behaviors. Our sample included 170 Black/African American participants who were randomly assigned to either the intervention condition (n = 84) or the wait-list control group (n = 86). Participants in the intervention condition reported more self-compassion, used more mindfulness, and had greater self-efficacy using mindfulness; yet, no other differences were evident. Participants expressed high levels of satisfaction with the app and gave it a positive rating for its relevance to their lives. These findings support the efficacy of a culturally responsive mindfulness mHealth app to enhance self-compassion and increase the use of health-promoting behaviors, like mindfulness, among African Americans. Implications for future research are discussed.