Background: One of the most prevalent chronic illnesses in the nation and the world is diabetes. It remains as one of the leading cause of death so it's important to create cutting-edge, potentially cost-effective co-treatment techniques derived from plants that don't have any negative impacts. Previous research has shown that watercress (Nasturtium officinale) possesses anti-inflammatory, antioxidant, and anti-diabetic properties. Objectives: to investigate the effects of watercress aqueous extract on gene expression of glucose transporter 4 (GLUT4) and 5' AMP-activated protein kinase (AMPK) in streptozotocin induced diabetic rats.  Materials and methods: Sixty healthy male albino rats were used in this study. Animals were split into four equal groups, each of 15 rats. Group 1: (Negative Control), Group 2: (Diabetes Positive Control injected with (45mg/kg body weight) Streptozotocin intraperitoneally), Group 3 (diabetic rats received 100 mg of watercress aqueous extract /Kg body weight for 8 weeks, daily) and Group 4 (diabetic rats received 200 mg of watercress aqueous extract /Kg body weight for 8 weeks, daily). Blood was collected after scarification on weeks 2, 4, 6, and 8 of the experiment for serum separation and pancreatic tissues were collected on weeks 4 and 8 of the experiment.  Fasting blood glucose as measured by glucometer, insulin hormone was measured by ELISA kit.Triglyceride, LDL, HDL, creatinine, urea, AST and ALT were measured by spectrophotometer. SYBR Green qPCR Master Mix was used for measurement of GLUT4, AMPK and Beta-actin.   Results: The treated group exhibited a significant and progressive decrease in fasting blood glucose, triglycerides, total cholesterol, LDL, HDL, creatinine, urea, ALT, and AST and a significant and progressive increase in insulin hormone at all experiment times compared to the controls. The 4th group exhibited a significant and progressive up regulation gene expression of GLUT4 and AMPK genes at 4 and 8 weeks compared to the controls considering watercress as an alternative treatment for diabetes. Conclusion. Watercress aqueous extract had positive effects on lowering and maintaining normal glucose levels.