Plant-based diets have emerged as a promising approach for the prevention of cardiometabolic diseases (CMDs), yet questions remain regarding the quality of plant-based foods, underlying biological mechanisms, and population-wide applicability. This thesis investigates the associations between plant-based diet quality and cardiometabolic health using large-scale prospective cohort data, integrating traditional biomarkers with systems-level insights from metabolomics and gut microbiome profiling. Higher adherence to healthy plant-based diets was associated with lower cardiovascular disease risk and favorable longitudinal changes in cardiometabolic markers, whereas unhealthy plant-based diets were linked to higher risk and less favorable biomarker profiles. Metabolomic analyses revealed distinct plasma signatures for healthy versus unhealthy plant-based diets, reflecting differences in lipid, glucose, and HDL-related metabolites. Microbiome analyses demonstrated that healthy diets were associated with greater microbial diversity, increased short-chain fatty acid–producing taxa, and higher circulating betaine, whereas unhealthy diets showed less favorable microbial profiles. Furthermore, individuals with high genetic risk for coronary heart disease who adhered to healthy lifestyle behaviors, including a high-quality plant-based diet, experienced a substantially reduced disease risk. Overall, these findings highlight the importance of distinguishing diet quality in plant-based eating, support lifestyle-based prevention strategies, and underscore the potential of multi-omics approaches to inform precision nutrition and translational research.