Globally, diabetes mellitus (DM) disease is one of the main causes of death. Type-2 diabetes mellitus (T2-DM) cannot be cured by first-line medications, and long-term use carries a significant risk of serious side effects. Novel antidiabetic agents with high efficacy are required. In the T2-DM rats' model, the anti-diabetic effect of Rhopilema nomadica venom (RNV) and R. nomadica umbrellar extracts (RNUE) was assessed. Biometric and biochemical measurements were determined. The median lethal doses (LD₅₀) of RNV and RNUE were estimated, and then Sprague Dawley male rats were split into five groups (n=10) as follows; group 1 (Gp1) served as a negative control. Gp2 to Gp5 were given a high-fat diet (HFD) and then, injected with STZ (30 mg/kg) interperitoneal (i.p.). Gp2 was kept as diabetic rats (T2-DM rats). Metformin (Met) (150 mg/kg), RNV (7.5 mg/kg), and RNUE (14.4 mg/kg) were given to Gp3, Gp4, and Gp5, respectively. All treatments were taken i.p., once every day for eight weeks body weight (b.wt) changes, the levels of glucose, C-peptide, biochemical parameters, and the histopathological alterations were assessed. R. nomadica diameter was 35- 40 cm, and its weight was 4- 4.5 kg. RNV and RNUE total antioxidant capacities were 2.39 ± 0.18 and 2.92 ± 0.26 mg/g. RNV and RNUE protein profiles showed eight and seven bands. Treatment of T2-DM rats with Met or RNUE led to a hypoglycemic effect as indicated by improvement of b.wt changes, glucose, C-peptide levels, hepato-renal function, antioxidant/oxidant biomarkers status, and insulin-secreting β-cells in the pancreatic islets.