Hypertension is a major cardiovascular problem resulting in significant mortality. Cissus quadrangularis having several pharmacological effects has not been evaluated for its ability to modulate blood pressure. Thus, the ability of C. quadrangularis aqueous extract (CQE) to modulate blood pressure was evaluated in normotensive and angiotensin II-induced hypertensive rats under urethane anesthesia. The animals were divided into four groups namely, control (saline injection), CQE (extract alone, 10 mg/kg), Ang II (Ang II alone, 0.5 µg/kg) and Ang II + CQE (Ang II + extract). All treatments were delivered by intravenous route and in Ang II + CQE group, Ang II was injected 30 min after injection of the extract. Hemodynamic parameters, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), and heart rate (HR) were recorded by the BIOPAC system after the cannulation of the carotid artery and jugular vein. The results indicated that CQE lowered SBP, DBP, MABP and heart rate to varying degrees in normotensive rats compared to control groups. In case of angiotensin II-induced hypertension, CQE administration resulted in substantial decrease in SBP, DBP, and MABP which were raised by Ang II. CQE reduced SBP, DBP, and MABP by 12, 59, and 11%, respectively. It is worth noting that, while SBP was not brought down to baseline levels by CQE, DBP was, suggesting significant hypotensive/antihypertensive activity of CQE. Further research is required to determine the molecular mechanism of C. quadrangularis extract’s hypotensive/antihypertensive action and to conduct clinical trials to establish its optimal use as an antihypertensive therapeutic.