The present study describes the synthesis of novel chalcone based 1-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl} thioureas (4a-c) using Claisen Schmidt condensation and investigates their protective role in diabetic conditions and associated oxidative stress. Spectral properties for the synthesized compounds were studied. Novel compounds were screened for antihyperglycemic effect in streptozotocin (STZ)-induced diabetic rats in a 6 week study and compound 4b exhibited significant (p ≤ .05) results similar to the standard drug glipizide. Treatment of diabetic animals with compound 4b (10 and 20 mg/kg, body weight) for 12 weeks, reduced the increased blood glucose level significantly (p ≤ .01) and restored attenuated serum biochemical parameters to normal levels. Altered antioxidant enzyme activity was also considerably (p ≤ .01) restored to the standard normal range. β-apoptotic TUNEL assay indicated that compound 4b (AI: 1.2 ± 0.05) could prevent further β-cell death in the pancreas of diabetic animals in a dose-dependent manner, which highlights its potentiality as an effective antihyperglycemic agent.