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BackgroundDepression and other mental health disorders are prevalent among people living with chronic health conditions. Although digital cognitive behavioral therapy (CBT) is considered an effective treatment, African American individuals are less likely to engage in and adhere to digital therapies for mental health disorders compared with White individuals. ObjectiveThe aim of this study was to understand digital CBT mental health treatment perceptions and preferences of African American individuals with sickle cell disease (SCD). MethodsAfrican American individuals with SCD from various US locations were invited to participate in a series of focus groups. Participants were introduced to a health coach–supported mental health app and then asked a series of questions about the usability and appeal of the program as well as, more generally, what would make a digital mental health program effective for them. The authors reviewed the focus group transcripts and conducted a qualitative analysis of the results. ResultsA total of 25 people participated in 5 focus groups. Overall, 5 primary themes emerged regarding how app content and related coaching could be modified to enhance digital CBT engagement. These themes included connection with others living with SCD, the personalization of app content and coaching, characteristics of coaches, journaling and pain tracking, and considerations for optimal engagement. ConclusionsEnhancing the user experience by making digital CBT tools relevant to patient populations is critical for optimizing program engagement and its uptake. Our findings highlight potential strategies to modify and design digital CBT tools for users with SCD and may also be applicable to patients with other chronic conditions. Trial RegistrationClinicalTrials.gov NCT04587661; https://clinicaltrials.gov/ct2/show/NCT04587661