Background: Renal denervation (RDN) lowers blood pressure (BP) in patients with uncontrolled hypertension. Limited data exist on the effectiveness of different antihypertensive medications following RDN on BP and maladaptive cardiac phenotypes. Methods: Eighty-nine male spontaneously hypertensive rats with continuous BP recording underwent RDN or sham operation. Ten days postsurgery, spontaneously hypertensive rats were randomized to receive no antihypertensive medication, amlodipine, olmesartan, hydrochlorothiazide, bisoprolol, doxazosin, or moxonidine for 28 days. Cardiac remodeling was determined histologically, and activation of the renin-angiotensin-aldosterone system was explored. Results: Before initiation of antihypertensive drugs, RDN reduced mean arterial pressure (−12.6 mm Hg [95% CI, −14.4 to −10.8]; P <0.001). At study end, mean arterial pressure was lower in RDN compared with sham operation in drug-naïve controls ( P =0.006), olmesartan ( P =0.002), amlodipine ( P =0.0004), hydrochlorothiazide ( P =0.006), doxazosin ( P = 0.001), and bisoprolol ( P =0.039) but not in animals receiving moxonidine ( P =0.122). Compared with pooled BP change of all other drug classes, mean arterial pressure change was largest for olmesartan (−15.9 mm Hg [95% CI, −18.6 to −13.2]; P <0.001) and amlodipine (−12.0 mm Hg [95% CI, −14.7 to −9.3]; P <0.001). In drug-naïve controls, RDN reduced plasma renin activity (−5.6%¸ P =0.03) and aldosterone concentration (−53.0%; P =0.005). In the presence of antihypertensive medication, plasma renin activity and aldosterone remained unchanged after RDN. Cardiac remodeling was not affected by RDN alone. In animals receiving olmesartan after RDN, cardiac perivascular fibrosis was attenuated. Amlodipine and bisoprolol following RDN reduced cardiomyocyte diameter. Conclusions: Following RDN, treatment with amlodipine and olmesartan resulted in the largest BP reduction. Antihypertensive medications mediated heterogeneous effects on renin-angiotensin-aldosterone system activity and cardiac remodeling.