High-energy intake causes imbalances in nutrient homeostasis contributing to a high prevalence of metabolic chronic diseases. The extent to what metabolic imbalances can be ameliorated by the inclusion of immunonutritional ingredients obtained from flours favouring nutrient and calorie management remains poorly understood. Herein, it is demonstrated that partial replacement of wheat flour (WB) with that from Chenopodium quinoa varieties [red (RQ, 25% w/w) and white (WQ, 25% w/w)] as well as from Salvia hispanica L., [whole (Ch, 20% w/w) and semi-defatted (Ch_D, 20% w/w)] in bread formulations ameliorates the metabolic and inflammation consequences of high-fat diet consumption in hyperglycaemic animals. Feeding animals with bread formulations replacing wheat flour effectively reduced insulin resistance (by 2-fold, HOMAir). The reduction in starch content did not appear as a determinant of controlling HOMAir. Only animals fed with RQ and Ch diet displayed increased plasma levels of triglycerides, which significantly contributed to mitigate HFD-induced hepatic lipid peroxidation. The latter was increased in animals receiving Ch_D diet, where PUFAs were eliminated from chia’s flour. Feeding with WQ and Ch samples caused an upward trend in hepatic TNF-α and IL-6 levels. Despite similarities between immunonutritional agonists in animals fed with RQ and WQ, IL-17 levels were quantified higher for animals fed with WQ. All bread formulations except Ch_D samples significantly increased the hepatic granulocyte–monocyte colony stimulation factor levels. These results indicated that replacement of wheat flour with that from quinoa and chia improved the metabolic imbalances in hyperglycaemic animals.