Dietary plant bioactives, and in particular flavonoids, can exert actions at the gastrointestinal (GI) tract that can have an impact systemically, e.g. on glucose homeostasis, lipid and energy metabolism. GI barrier permeabilization and the associated increased passage to the circulation of luminal endotoxins underlie in part the pathophysiology of obesity-associated pathologies, including insulin resistance and type 2 diabetes. Endotoxins trigger systemic pro-inflammatory responses that contribute to tissue insulin resistance involving the activation of redox-regulated signals. Among flavonoids, we found that the flavan-3-ol (-)-epicatechin (EC) inhibits high fat (HFD)- and/or high fructose (HFr) diet-induced insulin resistance and steatosis in rodents. These beneficial effects are associated with EC capacity to inhibit HFD-mediated intestinal barrier permeabilization and endotoxemia. In vivo and in vitro studies support intestinal cell NADPH oxidase as a major target involved in EC effects. NADPH oxidase triggers a downstream series of events that cause tight junction disruption: NF-kB and ERK1/2 activation, upregulation of myosin light chain (MLC) kinase, leading to MLC phosphorylation and consequent monolayer permeabilization. Modulation of NADPH oxidase is also involved in the capacity of EC to restore insulin sensitivity in liver and adipose tissues, given that the redox-regulated activation of IKK/NF-kB, JNK1/2 and PKC causes inhibitory serine phosphorylation of the insulin receptor (IR) substrate 1 (IRS1), and upregulation of the IR and IRS1 inhibitory tyrosine phosphatase PTP1B. EC and other structurally related flavonoids (i.e. anthocyanidins (AC)) that directly inhibit NADPH oxidase, share similar chemical structures and capacity to improve insulin sensitivity. Furthermore, inhibition of NF-kB can explain EC-mediated decreased expression of select NADPH isoforms. In summary, the capacity of select bioactives (EC, AC) to improve HFD/HFR-associated insulin resistance is in part mediated through their capacity to modulate NADPH oxidase and redox-regulated pathways, leading to loss of GI tract barrier integrity and downregulation of the insulin pathway.