Despite high prevalence of obesity and polypharmacy among African American (AA) older adults, little information exists on the associations between the two in this population. This study explored the association between obesity and polypharmacy among AA older adults who were residing in poor urban areas of South Los Angeles. We also investigated role of gender as the moderator and multimorbidity as the mediator of this association. In a community-based study in South Los Angeles, 308 AA older adults (age ≥ 55 years) were entered into this study. From this number, 112 (36.4%) were AA men and 196 (63.6%) were AA women. Polypharmacy (taking 5+ medications) was the dependent variable, obesity was the independent variable, gender was the moderator, and multimorbidity (number of chronic medical conditions) was the mediator. Age, educational attainment, financial difficulty (difficulty paying bills, etc.), income, marital status, self-rated health (SRH), and depression were the covariates. Logistic regressions were used for data analyses. In the absence of multimorbidity in the model, obesity was associated with higher odds of polypharmacy in the pooled sample. This association was not significant when we controlled for multimorbidity, suggesting that multimorbidity mediates the obesity-polypharmacy link. We found significant association between obesity and polypharmacy in AA women not AA men, suggesting that gender moderates such association. AA older women with obesity are at a higher risk of polypharmacy, an association which is mainly due to multimorbidity. There is a need for screening for inappropriate polypharmacy in AA older women with obesity and associated multimorbidity.