The oxidative stress plays a critical role in the progression of diabetes mellitus (DM) and its complications. Corn silk is a traditional medicine used to treat DM. The aim of this study is to investigate the antioxidant capacity of corn silk, as well as its inhibitory potential on DM and diabetic nephropathy (DN). The ethanol extract of corn silk (CS) was liquid-liquid fractionated to get petroleum ether fraction (PCS), ethyl acetate fraction (ECS), n-butanol fraction (BCS) and water fraction (WCS). The Folin-Ciocalteu and AlCl₃ assay showed that silk corn contained considerable amount of phenolics and flavonoids, ECS and BCS were the two phenolic-enriched fractions with highest TPC and TFC values. The ECS and BCS showed the highest total antioxidant activity and reducing power, as well as the strongest scavenging activity against DPPH and hydroxyl radicals, compared to CS and other fractions. The ECS and BCS displayed appreciable anti-hyperglycaemic effect indicated by the significant inhibition on α-amylase and α-glucosidase in enzymatic assays. In BSA-glucose model, ECS and BCS effectively inhibited the formation of advanced glycation end products (AGEs). In addition, the anti-diabetic nephropathy activity assay displayed that CS, ECS and BCS significantly inhibited the production of Col IV, FN and IL-6 in high-glucose stimulated mesangial cells at 200 μg/mL. These findings suggested the antioxidant activities of corn silk could contribute, at least in part, to its traditionally claimed therapeutic benefits on DM and DN. The phenolic-enriched CS fractions could be considered as a source of natural antioxidants and further developed for the prevention and treatment of DM and its complications including DN.