Background.Little is known about how physical activity influences the relationship between neuroticism and cognitive function and cognitive decline.Methods.Data from the Chicago Health and Aging Project (CHAP) was utilized to conduct this study. CHAP is a population-based cohort study of chronic conditions in older adults. Participants completed in-home interviews cycles of three years from 1993–2012. Mixed effects regression models were conducted to test the associations between physical activity, neuroticism, and the interaction between neuroticism and global cognitive function and global cognitive decline. Stratified mixed effects regression models by physical activity level were conducted to test the associations between neuroticism and global cognitive function and global cognitive decline.Results.A total of 7,685 participants were eligible for this study. Participants were 62% female and 64% African American. We found statistically significant associations for the interaction of medium physical and neuroticism (β = 0.014 (SE = 0.007), p = .037) and the interaction of high physical activity and neuroticism (β = 0.021 (SE = 0.007), p = .003) on global cognitive function at baseline but not for decline over time. Stratified analysis showed that among participants with high physical activity levels, the association between neuroticism and global cognitive decline was statistically significant (β=−0.002 (SE = 0.001), p = .023).Conclusion.Increasing physical activity level benefits the cognitive functioning of individuals with high neuroticism. Interventions should incorporate health behavior change approaches which aim to reduce characteristics of neuroticism.