Cholesterol is one of the triggers of oxidative stress in the pancreatic-β cell, generating high levels of reactive oxygen species, which leads to impairment of insulin synthesis and secretion. Bioactive compounds, such as citrus flavanones, which possess anti-inflammatory and antioxidant activities, could reduce oxidative stress in β-cells and improve their function. We describe for the first time the protective effects of the phase-II flavanone metabolites [naringenin 7-O-glucuronide, hesperetin 3'-O-glucuronide, and hesperetin 7-O-glucuronide], and two flavanones-catabolites derived from gut microbiota metabolism [hippuric acid and 3-(4-hydroxyphenyl)propionic acid], on pancreatic β-cell line MIN6 under oxidative stress, at physiologically relevant concentration. Cholesterol reduced cell viability in a dose and time-dependent manner, with an improvement in the presence of the metabolites. Moreover, flavanone metabolites attenuated oxidative stress by reducing levels of lipid peroxides, superoxide anions, and hydrogen peroxide. In response to the reduction of reactive oxygen species, a decrease in superoxide dismutase and glutathione peroxidase activities was observed; these activities were elevated by cholesterol. Moreover, all the flavanone metabolites improved mitochondrial function and insulin secretion, and reduced apoptosis. Flavanone metabolites were found uptake by β-cells, and therefore could be responsible for the observed protective effects. These results demonstrated that circulating phase-II hesperetin and naringenin metabolites, and also phenolics derived from gut microbiota, protect pancreatic-β cells against oxidative stress, leading to an improvement in β-cell function and could be the bioactive molecules derived from the citrus consumption.