Adequate fruit and vegetable (F and V) intake, as recommended by the World Health Organization (over 400 g/day), is linked to reduced chronic disease risk. However, human intervention trials, especially with whole F and V and in complex combinations, are lacking. The MiBlend Study explored the effects of various phytochemical-rich F and V combinations on chronic disease risk markers, phytochemical absorption, and gene expression in blood. This randomized cross-over study involved participants consuming two of seven different F and V blends for 2 weeks (450 g/day), following a 2-week low F and V intake period (50 g/day). Each blend represented major phytochemical classes (flavonoids, anthocyanins, carotenoids, and glucosinolates) or combinations thereof. Markers of chronic disease risk, including DNA damage, oxidative stress, and retinal microvasculature, were measured. Increasing F and V intake significantly improved plasma antioxidant capacity, DNA damage protection, and retinal arteriolar dilation. Flavonoid-rich, carotenoid-rich, and complex blends notably reduced DNA damage susceptibility. Anthocyanin-rich and carotenoid-rich interventions were most effective in boosting antioxidant capacity, while blends high in flavonoids, especially combined with anthocyanins, significantly improved retinal microvasculature. Gene expression analysis revealed changes in DNA repair, signal transduction, and transcription processes, indicating mechanisms for these health benefits. The study suggests specific F and V blends can provide targeted health improvements, emphasizing the importance of both overall F and V intake and the specific phytochemical composition for personalized preventive strategies.