AbstractBone undergoes constant remodeling by osteoclast bone resorption coupled with osteoblast bone formation at the bone surface. A third major cell type in the bone is osteocytes, which are embedded in the matrix, are well‐connected to the lacunar network, and are believed to act as mechanical sensors. Here, it is reported that sympathetic innervation directly regulates lacunar osteocyte‐mediated bone resorption inside cortical bone. It is found that sympathetic activity is elevated in different mouse models of bone loss, including lactation, ovariectomy, and glucocorticoid treatment. Further, during lactation elevated sympathetic outflow induces netrin‐1 expression by osteocytes to further promote sympathetic nerve sprouting in the cortical bone endosteum in a feed‐forward loop. Depletion of tyrosine hydroxylase‐positive (TH+) sympathetic nerves ameliorated osteocyte‐mediated perilacunar bone resorption in lactating mice. Moreover, norepinephrine activatesβ‐adrenergic receptor 2 (Adrb2) signaling to promote secretion of extracellular vesicles (EVs) containing bone‐degrading enzymes for perilacunar bone resorption and inhibit osteoblast differentiation. Importantly, osteocyte‐specific deletion of Adrb2 or treatment with aβ‐blocker results in lower bone resorption in lactating mice. Together, these findings show that the sympathetic nervous system promotes osteocyte‐driven bone loss during lactation, likely as an adaptive response to the increased energy and mineral demands of the nursing mother.