The neuroanatomical basis behind acupuncture practice is still poorly understood. Here, we used intersectional genetic strategy to ablate NPY+ noradrenergic neurons and/or adrenal chromaffin cells. Using endotoxin-induced systemic inflammation as a model, we found that electroacupuncture stimulation (ES) drives sympathetic pathways in somatotopy- and intensity-dependent manners. Low-intensity ES at hindlimb regions drives the vagal-adrenal axis, producing anti-inflammatory effects that depend on NPY+ adrenal chromaffin cells. High-intensity ES at the abdomen activates NPY+ splenic noradrenergic neurons via the spinal-sympathetic axis; these neurons engage incoherent feedforward regulatory loops via activation of distinct adrenergic receptors (ARs), and their ES-evoked activation produces either anti- or pro-inflammatory effects due to disease-state-dependent changes in AR profiles. The revelation of somatotopic organization and intensity dependency in driving distinct autonomic pathways could form a road map for optimizing stimulation parameters to improve both efficacy and safety in using acupuncture as a therapeutic modality. Display omitted •Intersectional genetic manipulation of NPY+ sympathetic cells•Electroacupuncture stimulation (ES) drives distinct sympathetic pathways•ES operates in somatotopy- and intensity-dependent manners•NPY+ noradrenergic neurons bidirectionally modulate systemic inflammation Liu et al. reveals a neuroanatomical basis for acupuncture practice, showing that electroacupuncture stimulation can drive distinct autonomic pathways and modulate systemic inflammation in somatotopy-, stimulation-intensity-, and disease-state-dependent manners.