ObjectiveTo understand African Americans’ perceptions, barriers, and facilitators to recruitment, enrollment, adoption, maintenance, and retention in a nutrition and physical activity promotion program. DesignFour focus groups were conducted. SettingTwo community settings located in Jackson and Hattiesburg, Mississippi. ParticipantsParticipants (n = 28) were aged 18–50 years. Main Outcome Measure(s)Barriers and facilitators associated with healthy eating, physical activity, achieving a healthy weight, and participation in a health behavior change program. AnalysisA conventional thematic content analysis approach includes data familiarization, initial code generation, initial theme generation, themes review, and team review for finalization of themes. ResultsMajor themes related to health behaviors and participation in a behavior change program were identified by participants, including time constraints, costs, social support, consistency and self-efficacy, motivation for longevity and disease prevention, physical appearance, fear of injury/pain, social norms/stigma associated with outdoor physical activity, body criticism from family members, and having empathic and validating program staff support. Conclusions and ImplicationsSeveral social determinants of health were identified as essential considerations for promoting healthy nutrition and physical activity behaviors among African American adult Mississippians. Cultural and spiritual implications were also identified. Study insights inform policy approaches for designing culturally appropriate health behavior change programs in the Deep South.