Given that the Healthy Eating Index–2015 (HEI-2015) was altered from the HEI-2010 by reclassifying sources of dietary protein and substituting the empty calories component with two new components—saturated fats and added sugars—researchers undertook this prospective analysis involving participants (n = 12,413; aged 45–64 years; 56% women) from the Atherosclerosis Risk in Communities Study to investigate the association of HEI-2015 score, along with three other previously defined indices, with incident cardiovascular disease (CVD), CVD mortality, and all-cause mortality. A median of 24–25 years of follow-up revealed 4,509, 1,722, and 5,747 cases of incident CVD, CVD mortality, and all-cause mortality, respectively. Among US adults, lower risks of incident CVD, CVD mortality, and all-cause mortality were observed in correlation with higher adherence to the 2015–2020 Dietary Guidelines for Americans.