<p>The vagus nerve is one of the most widely distributed and functionally complex nerves in the body. It is closely associated with higher neurological functions such as motor control, learning, and memory. Increasing evidence also demonstrates that it plays a crucial role in immune regulation and anti-inflammatory responses. This review first describes the mechanisms by which the vagus nerve regulates autonomous anti-inflammatory immunity. These mechanisms include the cholinergic anti-inflammatory pathway (CAP), the hypothalamic–pituitary–adrenal (HPA) axis, the brain–spleen axis, the brain–gut axis, the modulation of immune cell activity, and the release of multiple neurotransmitters. Each of these pathways contributes to the regulation of peripheral inflammatory responses. Further analysis reveals that these pathways are not independent parallel mechanisms. Instead, they form an integrated neuro-immune-endocrine regulatory network. Within this network, the vagus nerve acts as a central hub. Peripheral inflammatory signals, sensed via the gut-brain axis or mediators, reach the Central Nervous System (CNS) through vagal afferents. This triggers dual pathways: HPA-mediated systemic tolerance and CAP-mediated local anti-inflammatory effects. Integrated with the brain-spleen axis, these mechanisms form a closed-loop network maintaining peripheral immune homeostasis. Additionally, this review compiles therapeutic drugs and traditional Chinese medicine (TCM) derivatives related to these mechanisms. We explore their mechanisms of action and potential value in treating peripheral inflammatory diseases. This discussion provides a theoretical basis for future anti-inflammatory and immunomodulatory drug development.</p> Graphical abstract <p>Therapeutic of Multi-Organ Inflammatory Diseases via Electrical Stimulation or Pharmacological Activation of the Vagus Nerve Immune Anti-Inflammatory Pathway. (All figures were drawn by figdraw.)</p>