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Recent evidence suggests that acetylcholine has a positive influence on bone mechanotransduction. Osteocytes express components for nicotinic acetylcholine receptors (nAChRs), which are known for mediating calcium signaling and may affect mechanosensitivity. Here, we use fluorescent imaging approaches to provide evidence of close spatial association between osteocytes and cholinergic nerve fibers in cortical bone in vivo. Moreover, we show that osteocytes are responsive to cholinergic signaling, influencing bone mechanoadaptation. We report sexually dimorphic patterns in bone structure and mechanobiology based on nAChR function. In females, osteocyte mechanosensitivity was decreased at small force magnitudes and tissue level deficits were recovered with anabolic loading. In males, osteocyte mechanosensitivity was increased in some groups and anabolic loading had very little effect on overall tissue architecture. This work establishes a previously unidentified paradigm wherein osteocytes interface with cholinergic nerves and bone mechanotransduction is regulated by osteocyte cholinergic signaling in a sexually dimorphic way.