Elevated postprandial glycemic responses (PPGRs) are associated with type 2 diabetes and cardiovascular disease. PPGRs to the same foods have been shown to vary between individuals, but systematic characterization of the underlying physiologic and molecular basis is lacking. We measured PPGRs using continuous glucose monitoring in 55 well-phenotyped participants challenged with seven different standard carbohydrate meals administered in replicate. We also examined whether preloading a rice meal with fiber, protein or fat ('mitigators') altered PPGRs. We performed gold-standard metabolic tests and multi-omics profiling to examine the physiologic and molecular basis for interindividual PPGR differences. Overall, rice was the most glucose-elevating carbohydrate meal, but there was considerable interindividual variability. Individuals with the highest PPGR to potatoes (potato-spikers) were more insulin resistant and had lower beta cell function, whereas grape-spikers were more insulin sensitive. Rice-spikers were more likely to be Asian individuals, and bread-spikers had higher blood pressure. Mitigators were less effective in reducing PPGRs in insulin-resistant as compared to insulin-sensitive participants. Multi-omics signatures of PPGR and metabolic phenotypes were discovered, including insulin-resistance-associated triglycerides, hypertension-associated metabolites and PPGR-associated microbiome pathways. These results demonstrate interindividual variability in PPGRs to carbohydrate meals and mitigators and their association with metabolic and molecular profiles.