Radiofrequency renal denervation (RF-RDN) inhibits the renin–angiotensin–aldosterone system and improves cardiovascular outcomes in a pig model of heart failure with reduced ejection fraction (HFrEF). Yucatan miniature pigs were subjected to 75 min of left anterior descending coronary artery balloon occlusion to induce a myocardial infarction, followed by 18 weeks of reperfusion. Animals with HFrEF (defined as a left ventricular (LV) ejection fraction <40%) were randomly assigned to receive bilateral RF-RDN (n = 10) or a sham procedure (n = 11) at 6 weeks after reperfusion. RF-RDN was associated with significant reductions in renal noradrenaline content, circulating angiotensin I and angiotensin II levels, LV end-systolic volume and LV fibrosis compared with controls. RF-RDN was also associated with significant increases in circulating B-type natriuretic peptide levels, LV longitudinal strain and LV ejection fraction. Moreover, RF-RDN improved coronary artery responses to vasodilators.