Tiliacora triandra (Colebr.) Diels (TT) is a native plant of Southeast Asia and widely use in northeastern Thai cuisines known as “Yanang”. Several studies have shown that leaves of TT extract (TTE) has various pharmacological effects, such as, anti-inflammatory, anti-cancer, anti-aging, anti-oxidant, anti-hypercholesterolemia, and inhibition of intestinal cholesterol absorption. However, the beneficial effects of TTE on hyperglycemia is limited. This study investigated the effects of TTE on antioxidant activity and anti-hyperglycemia against diabetes in rats. Free radical scavenging activities of TTE were determined using 2, 2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+) assays. Oral glucose tolerance test was used to screen anti-hyperglycemic effects in normal rats. Type 2 diabetic rats were induced by high-fat diet and a low-single dose of streptozotocin and supplemented with 250, 500, 1000 mg/kg BW of TTE daily for 12 weeks. Plasma biochemical parameters were analyzed. The mRNA expression of genes involved in oxidative stress including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) was evaluated using quantitative real-time PCR. Results show TTE exhibited free radical scavenging activities against DPPH• and ABTS•+. Acute anti-hyperglycemic effect of TTE was shown at 1000 mg/kg BW in normal rats. TTE also exerted anti-hyperglycemia, anti-hypercholesterolemia and improved glucose intolerance in type 2 diabetic rats. These TTE effects were corresponding to the significant reduction in mRNA expression of antioxidant genes (SOD, CAT and GPx). These findings suggest that TTE has anti-diabetic and anti-oxidant effects which could potentially be promoted into nutraceutical product for diabetes.