Accumulation of advanced glycation end products (AGEs) in the body is implicated in the pathogenesis of many diseases such as diabetes, cardiovascular diseases and atherosclerosis. Methylglyoxal (MGO), a major precursor of AGEs, has been reported to induce insulin resistance both in vitro and in vivo studies. Psoralea corylifolia seeds (PCS) has been used as a traditional medicine for numerous skin problems, such as leucoderma, skin rashes, infections, and others. The aim of this study was to investigate whether PCS extract attenuates insulin resistance induced by MGO. In the present study, PCS extract significantly improved MGO-induced insulin resistance in HepG2 cells, as indicated by an increase in phosphorylation of Akt and IRS-1/2, and glucose uptake in MGO-treated cells. Insulin resistance was induced in male C57BL/6N mice (6 weeks old) by administration of 1% MGO in drinking water for 18 weeks. Treatment with PCS extract (200 and 500 mg/kg) significantly improved glucose tolerance and insulin tolerance in MGO-administered mice. In addition, PCS extract significantly restored p-Akt and p-IRS1/2 expression in the liver of MGO-administered mice. We found that PCS extract significantly decreased the phosphorylation of ERK, p38 and NF-κB, and suppressed mRNA expression of pro-inflammatory cytokines, such as TNF-α, IL-1β, and iNOS in MGO-administered mice. Measurement of ROS production in HepG2 cells showed that PCS extract (50 – 500 µg/ml) reduce ROS production in MGO-treated cells. Moreover, we observed that GPx activity and protein levels of antioxidant enzymes, such as SOD1, SOD2 and HO-1, in the liver of MGO-administered mice were markedly enhanced by treatment with PCS extract. PCS extract also showed inhibitory effects on AGE formation induced by MGO in HepG2 cells and mouse serum. Taken together, we suggest that PCS extract ameliorates MGO-induced insulin resistance in HepG2 cells and mice by attenuating oxidative stress and inhibiting AGE formation.