Excess use of glucocorticoids either natural or synthetic has been associated with hypertension. Dexamethasone is a synthetic glucocorticoid with multiple uses. Recent studies demonstrated that dexamethasone induced hypertension is of endothelial dysfunction and decreased nitric oxide (NO) production. This work was designed to investigate the protective effect of L-arginine and ascorbic acid on dexamethasone induced hypertension in rats. Thirty adult male Albino rats were used in this study. Rats were equally divided into 5 groups: (G 1) Negative control group, (G 2): Positive hypertensive group, (G 3): L – arginine treated group, (G 4): Ascorbic acid treated group and (G 5): combined L-arginine and ascorbic acid treated group. L – arginine, ascorbic acid were given 2 weeks before induction of hypertension. Rats were followed up by measuring arterial blood pressure, Nitric oxide in urine and tissue homogenate, Total antioxidant capacity in serum and histopathology. Dexamethasone increased systolic (260.16 ± 28.9 mmHg) and diastolic blood pressure (149.8 ± 7.22 mmHg), decaresed NO in tissue (72.1 ± 5.2 μmol/ g (and urine (0.26 ± 0.04 μmol/ 24h(. Combination between L-arginine and ascorbic acid normalized systolic (118.6 ± 5.3 mmHg) and diastolic (79.5 ± 5.04 mmHg ) blood pressure and increased NO in aortic tissue (135.5 ±7.1μmol/ g) and urine (0.6 ± 0.08 μmol/ 24h) denoting that combination between L-arginine and ascorbic acid could effectively prevent dexamethasone induced hypertension