Dietary and lifestyle evolutionary discordance is hypothesized to play a role in the etiology of cardiovascular disease (CVD), including coronary heart disease (CHD), and stroke. We aimed to investigate associations of a previously-reported, total (dietary plus lifestyle) evolutionary-concordance (EC) pattern score with incident CVD, CHD, and stroke. We used multivariable Cox proportional hazards regression to investigate associations of the EC score with CVD, CHD, and stroke incidence among United States Black and White men and women ≥ 45 years old in the prospective REasons for Geographic and Racial Differences in Stroke (REGARDS) study (2003-2017). The EC score comprised seven equally-weighted components: a previously-reported dietary EC score (using Block 98 food frequency questionnaire data) and six lifestyle characteristics (alcohol intake, physical activity, sedentary behavior, waist circumference, smoking history, and social network size). A higher score indicates a more evolutionary-concordant dietary/lifestyle pattern. Of the 15,467 participants in the analytic cohort without a CVD diagnosis at baseline, 1,563 were diagnosed with CVD (967 with CHD and 596 with stroke) during follow-up (median 11.0 years). Among participants in the highest relative to the lowest EC score quintile, the multivariable-adjusted hazards ratios and their 95% confidence intervals for CVD, CHD, and stroke were, respectively, 0.73 (0.62, 0.86; P trend < 0.001), 0.72 (0.59, 0.89; P trend < 0.001), and 0.76 (0.59, 0.98; P trend = 0.01). The results were similar by sex and race. Our findings support that a more evolutionary-concordant diet and lifestyle pattern may be associated with lower risk of CVD, CHD, and stroke.