Abstract Adherence to a healthy lifestyle—characterized by abstaining from smoking, being physically and cognitively active, having a high-quality diet, and limiting alcohol use—is associated with slower cognitive decline in older adults, but whether this relationship extends to persons with a genetic predisposition (e.g., carriers of the ε4 allele of the apolipoprotein E gene (APOE*E4)) remains uncertain. Using data from a population-based study, the Chicago Health and Aging Project (Chicago, Illinois), we followed 3,886 individuals who underwent regular clinical and cognitive assessments from 1993 to 2012. Of 3,886 older adults, 1,269 (32.7%) were APOE*E4 carriers. Compared with noncarriers, APOE*E4 carriers had faster cognitive decline (β = −0.027 units/year, 95% confidence interval (CI): –0.032, −0.023). In contrast, persons with 2–3 and 4–5 healthy lifestyle factors had slower cognitive decline (β = 0.008 units/year (95% CI: 0.002, 0.014) and β = 0.019 units/year (95% CI: 0.011, 0.026), respectively) compared with those with 0–1 factor. In analyses stratified by APOE*E4 status, adherence to a healthy lifestyle (e.g., 4–5 factors vs. 0–1 factors) was associated with a slower rate of cognitive decline in both APOE*E4 carriers (β = 0.029, 95% CI: 0.013, 0.045) and noncarriers (β = 0.013, 95% CI: 0.005, 0.022). These results underscore the impact of a healthy lifestyle on cognition, particularly among persons with a genetic predisposition, who are more vulnerable to cognitive decline as they age.