Both lower life satisfaction (LLS) and chronic inflammation are underlying conditions for numerous diseases. We investigated their associations in African American adults, within the context of three hypotheses: (a) perceived LLS will be positively associated with inflammation measured by serum C-reactive protein (CRP); (b) this association will be mediated by body adiposity; and (c) these associations will be moderated by sex. Participants (n = 83; >45 years; 59% women) were a subsample of a larger church-based intervention to reduce cardiovascular risks and were assessed at baseline and after 6 months. Body adiposity (BMI/hip/waist circumferences) was measured by standardized methods and CRP with ELISA. LLS was self-reported. The analyses were conducted in the structural equation modeling (SEM) framework. The direct relationship between LLS and CRP was significant for all participants but was mediated by BMI/hip/waist circumferences. Multi-group SEM analysis provided evidence for sex moderation by showing that the mediating pathway from LLS to CRP through BMI, and to a lesser extent through hip/waist circumferences, was significant only in women. In conclusion, perceived LLS was positively associated with the level of inflammation mediated by BMI/hip/waist circumference, with the association between LLS and CRP being stronger in women. These findings contribute to the current literature untangling mediation/moderation processes in which perceived LLS may contribute to adiposity-related inflammation. They also add to precision medicine development, suggesting that stress and inflammation-reducing interventions should focus on African Americans, particularly women.