Radio-frequency renal denervation (RDN) therapy is under investigation for the treatment of uncontrolled hypertension. Data in hypertensive, drug-naïve large animal models using RDN is limited. A cohort of Ossabaw swine (N = 9) was implanted with telemetry monitors, enrolled on a high calorie-feed regimen and randomly assigned to RDN. Blood pressure (BP) data were separated and analyzed according to the following epoch definitions: 24-h (h), most-active-h, light-h, and dark-h. The mean weight increased by 45% from 86.5 ± 2.5 kg at telemetry implant (day 87) to 125.2 ± 4.5 kg at time of RDN therapy (day 227). Hypertension developed in all swine (24-h BP: 169.5/128.3 ± 5.8/5.1 mmHg pre-RDN). RDN resulted in significant reductions in noradrenaline kidney tissue concentration by 63%. Significant BP reductions were documented at 45 days post-RDN in all defined interday epochs, except for the dark-h period. The most pronounced SBP/DBP reduction was 12.4/11.2 mmHg (P < 0.05), observed during the most-active-h period. Animals continued to gain weight after the RDN procedure to the end of the study at 90 days (125.2 ± 4.5-138.5 ± 6.6 kg, P < 0.001). At 90 days post-RDN, the mean 24-h BP returned near pre-RDN baseline values. Given the strong relationship of BP to weight (R = 0.87, P < 0.001), group mean SBP/DBP was normalized by weight resulting in significant and continued reductions at both 45 and 90 days post-RDN across all intradaily epochs. Catheter-based RDN, using a multielectrode system, resulted in a significant reduction in 24-h BP in this drug-naïve, hypertensive animal model.