Background. Metabolic Syndrome (MetS), a major worldwide concern for the public health system, refers to a cluster of key metabolic components, and represents a risk factor for diabetes and cardiovascular diseases. As oxidative stress (OxS) and inflammation are the major triggers of insulin resistance (IR), the central aim of the present work is to determine whether glycomacropeptide (GMP), a milk-derived bioactive peptide, exerts beneficial metabolic effects. Methods. Intestinal Caco-2/15 cells are used to evaluate the role of GMP preventive actions against OxS and inflammation induced by iron-ascorbate (Fe/Asc). Results. The administration of GMP significantly reduces malondialdehyde, a biomarker of lipid peroxidation and raises superoxide dismutase 2 and glutathion peroxidase via the induction of nuclear factor erythroid 2–related factor 2, a transcription factor, which orchestrates cellular antioxidant defenses and maintains redox homeostasis. Similarly, GMP markedly lowers the inflammatory agents tumor necrosis factor-α and cyclooxygenase-2 via abrogation of the nuclear transcription factor- kB. Moreover, GMP-treated cells show a down-regulation of Fe/Asc-induced mitogen activated protein kinase pathway, suggesting lesser IR. Finally, GMP exhibits potency to decrease the production of lipoproteins chylomicrons, very low-density lipoprotein and low-density lipoprotein in Caco-2/15 cells. Conclusions. Our results highlight the effectiveness of GMP in attenuating OxS, inflammation, IR and lipoprotein biogenesis, which represent key components of MetS. Further investigation is needed to elucidate the mechanisms mediating the preventive action of GMP.