ABSTRACT The autonomic nervous system plays a crucial role in regulating physiological processes and maintaining homeostasis through its two branches: the sympathetic nervous system and the parasympathetic nervous system. Dysregulation of the autonomic system, characterized by increased sympathetic activity and reduced parasympathetic tone, is a common feature in chronic kidney disease (CKD) and cardiovascular disease. This imbalance contributes to a pro-inflammatory state, exacerbating disease progression and increasing the risk for cardiovascular events. The sympathetic system promotes inflammation by releasing catecholamines, which activate adrenergic receptors on immune cells. The parasympathetic system exerts anti-inflammatory effects via the cholinergic anti-inflammatory pathway mediated by the vagus nerve. Targeting the autonomic system to restore the balance between the sympathetic and the parasympathetic components offers promising approaches to reduce inflammation and improve outcomes in CKD and cardiovascular disease. β-Blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers are pharmacological agents that modulate sympathetic activity and have shown anti-inflammatory effects. Lifestyle interventions, such as a healthy diet, physical exercise, mindfulness, and meditation, enhance parasympathetic activity and improve autonomic function. Vagus nerve stimulation has emerged as a promising therapy, demonstrating significant potential in reducing inflammation and improving clinical outcomes in various conditions, including CKD, myocardial infarction, and stroke. Despite mixed results in heart failure trials, vagal nerve stimulation has consistently improved quality-of-life measures. Understanding the mechanisms underlying autonomic system regulation of inflammation can inform the development of novel therapeutic strategies to restore autonomic balance and improve patient outcomes in CKD and cardiovascular disease.