The Healthy Eating Index–2015 (HEI-2015) score measures adherence to recommendations from the 2015–2020 Dietary Guidelines for Americans. The HEI-2015 was altered from the HEI-2010 by reclassifying sources of dietary protein and replacing the empty calories component with 2 new components: saturated fats and added sugars. Our aim was to assess whether the HEI-2015 score, along with 3 other previously defined indices, were associated with incident cardiovascular disease (CVD), CVD mortality, and all-cause mortality. We conducted a prospective analysis of 12,413 participants aged 45–64 y (56% women) from the Atherosclerosis Risk in Communities (ARIC) Study. The HEI-2015, Alternative Healthy Eating Index–2010 (AHEI-2010), alternate Mediterranean (aMed) diet, and Dietary Approaches to Stop Hypertension Trial (DASH) scores were computed using the average dietary intakes of Visits 1 (1987–1989) and 3 (1993–1995). Incident CVD, CVD mortality, and all-cause mortality data were ascertained from baseline through 31 December, 2017. We used Cox proportional hazards models to estimate HRs and 95% CIs. There were 4509 cases of incident CVD, 1722 cases of CVD mortality, and 5747 cases of all-cause mortality over a median of 24–25 y of follow-up. Compared with participants in the lowest quintile of HEI-2015, participants in the highest quintile had a 16% lower risk of incident CVD (HR: 0.84; 95% CI: 0.76–0.93; P-trend < 0.001), 32% lower risk of CVD mortality (HR: 0.68; 95% CI: 0.58–0.80; P-trend < 0.001), and 18% lower risk of all-cause mortality (HR: 0.82; 95% CI: 0.75–0.89; P-trend < 0.001) after adjusting for demographic and lifestyle covariates. There were similar protective associations for AHEI-2010, aMed, and DASH scores, and no significant interactions by race. Higher adherence to the 2015–2020 Dietary Guidelines for Americans was associated with lower risks of incident CVD, CVD mortality, and all-cause mortality among US adults.