Endothelial dysfunction is related to the reduced bioavailability of nitric oxide (NO) and plays a significant role in developing hypertension. The intake of a diet rich in antioxidants decreases the threat of hypertension. Cissus quadrangularis possesses antioxidant, anti-inflammatory, and hypocholesterolemic activities. However, to date, no studies have been performed to explore this plant's antihypertensive and vasorelaxant activity. Herein, we investigated the chronic effect of C. quadrangularis on blood pressure as well as vascular function in hypertensive rats. Male spontaneously hypertensive rats (SHR) were randomly divided into two groups. Normotensive Wistar rats were taken as the control group. The treatment was done using ethanolic extract of C. quadrangularis (EECQ) at a dose of 200 mg/kg. The administration of EECQ for six weeks reduced the systolic blood pressure, mean arterial blood pressure, and heart rate. It also alleviated the cardiac and renal hypertrophy indices. Supplementation of EECQ improved the endothelium-dependent aortic vasodilation induced by acetylcholine. It restored the NO level and endothelial NO synthase expression in the aorta. Subsequently, the extract alleviates the oxidative stress and inflammatory markers in SHR rats. Thus, in the present study, the chronic treatment of EECQ to genetically hypertensive rats improved endothelium-dependent relaxation in addition to its antihypertensive effect by eNOS activation and inhibition of ROS production, inflammation.