Our present study examined the effects of heated, humidified, high nasal flow air therapy (HNF) in an ovine model of renovascular hypertension. HNF is commonly used in human patients to treat dyspnoea and respiratory failure. Previous research has indicated that the use of HNF improves oxygenation in respiratory diseases. It is known that the carotid body plays a role in mediating hypertension, although this is in the absence of low oxygenation levels. We hypothesized that HNF may lead to beneficial effects on vascular resistance and decrease mean arterial pressure (MAP). Experiments were conducted on conscious, adult female Romney sheep. Hypertension was surgically-induced via unilateral constriction of the renal artery (i.e., two-kidney, one-clip model; 2K1C). An incision was made over the flank contralateral to the clipped kidney to place an ultrasonic flow probe around the renal artery to measure renal blood flow (RBF). The common carotid artery was exposed, and a pressure catheter was inserted to record MAP. MAP, RBF, and calculated renal vascular conductance (RVC) were recorded during HNF administration. Heated and humidified gas was passed through a wide-bore nasal cannula (Optiflow™+ Nasal High Flow Cannula) connected to an AIRVO 2 humidification system (AIRVO™ 2 Fisher & Paykel). After 30-minutes of basal recording, the high nasal flow was started at 10L/min, 20L, 30L, and 40L/min, each for 25 minutes duration. Clipping of the renal artery increased resting MAP (91±5 vs. 131±6 mmHg), but there was no change in heart rate (HR) or RBF. HNF significantly decreased MAP (p<0.001) in both groups of animals (normotensive; from 91±5 to 85±4 mmHg, hypertensive; from 131±6 to 119±5 mmHg). RVC was increased in both normotensive and hypertensive sheep (p<0.05). There was no significant change in RBF in both groups. There was no change in heart rate in the hypertensive group, but there was a substantial decrease in heart rate in the normotensive group (p<0.01). Our data suggest that in an ovine model of hypertension, HNF leads to a substantial decrease in MAP. Whether HNF inhibits the peripheral chemoreflex remains to be determined in future studies. Taken together, these findings suggest improving oxygenation may offer clues to possible mechanisms of hypertension.