The sympathetic division of the autonomic nervous system plays a crucial role in maintaining homeostasis, but its overactivity is implicated in various pathological conditions, including hypertension, hyperglycaemia, heart failure, and rheumatoid arthritis. Traditional pharmacotherapies often face limitations such as side effects and poor patient adherence, thus prompting the exploration of device-based multi-organ denervation as a therapeutic strategy. Crucially, this procedure can potentially offer therapeutic benefits throughout the 24 h circadian cycle, described as an "always-on" effect independent of medication compliance and pharmacokinetics. In this comprehensive review, we evaluate the evidence behind targeted multi-organ sympathetic denervation by considering the anatomy and function of the autonomic nervous system, examining the evidence linking sympathetic nervous system overactivity to various cardiometabolic and inflammatory conditions and exploring denervation studies within the literature. So far, renal denervation, developed in 2010, has shown promise in reducing blood pressure and may have broader applications for conditions including arrhythmias, glucose metabolism disorders, heart failure, chronic kidney disease and obstructive sleep apnoea. We review the existing literature surrounding the denervation of other organ systems including the hepatic and splenic arteries, as well as the pulmonary artery and carotid body, which may provide additional physiological benefits and enhance therapeutic effects if carried out simultaneously. Furthermore, we highlight the challenges and future directions for implementing multi-organ sympathetic ablation, emphasising the need for further clinical trials to establish optimal procedural technique, efficacy and safety.