The study aimed to assess the trajectories of lifestyle characteristics and their association with 20-year cardiovascular disease (CVD) incidence. In 2002, 3042 Greek adults (aged: 45 (12) years) free of CVD were enrolled. In 2022, the 20-year follow-up was performed on 2169 participants; of those, 1988 had complete data for CVD. The 20-year CVD incidence was 3600 cases/10,000 individuals; the man-to-woman ratio was 1.25, with the peak difference in the 35-45 age group (i.e., 2.1); however, a reversal of the trend was observed in the age-groups 55-65 and 65-75, with a resumption of an almost equal incidence in those >75 years. In multi-adjusted analysis, age, sex, abnormal waist circumference, hypercholesterolemia, hypertension, and diabetes were positively associated with 20-year CVD risk, explaining 56% of the excess CVD risk, whereas an additional 30% was attributed to lifestyle trajectories; being physically active throughout life-course and being close to the Mediterranean diet were protective, while continuous smoking was detrimental against CVD risk. Mediterranean diet adherence protected against CVD development even if not sustained, while quitting smoking or engaging in physical activities during the 20-year observation did not offer any significant protection. A life-course personalized approach that is cost-effective and long-term sustained is needed to prevent CVD burden.