Regular daily intakes of whole grain products are associated with reduced risk of several diseases including type 2 diabetes. The health benefits of whole grains are linked to the existence of secondary bioactive metabolites including phenolic acids (PAs), flavonoids, and phytosterols. The production of these secondary metabolites in plants and the associated health properties is strongly dependent on the plant’s genetic and agro-climate environmental variations. Temperature as an abiotic factor has a powerful effect on a plant’s response to produce the secondary metabolites. Yet, how global warming influences wheat and other major crops’ secondary metabolite profiles and the associated health-promoting benefits remain unknown. The objective of this study was to investigate the genotypic and environmental factors that affect the production of wheat secondary metabolites and their associated health benefits. In the first phase of the present study, wheat varieties, representing different commercial classes, were grown at different geographical locations over two consecutive crop years. Genotypes and environment variations resulted in significant changes in wheat secondary metabolites’ levels and composition. Additionally, the impact of genotype, growth year and location variations on physiologic relevance was studied via investigating the ability of wheat’s phenolic acids to inhibit glucose uptake in a cell model of small intestinal transport. The degree of inhibition was defined by wheat genotype and growing environment conditions. In the second phase, we investigated if different growing temperatures could alter the accumulation of these secondary metabolites in different wheat varieties. Increased levels of phenolic acids and flavonoids were observed for wheat grains grown at higher temperatures. Extracts of wheat phenolics inhibited glucose accumulation in the CaCo-2 model of intestinal uptake, and this effect positively correlated with the phenolic contents and growth temperatures. The results offer a possible mechanism on how the addition of whole wheat products in the human diet improves postprandial glycemic responses through blunted glucose absorption.