Plasma calcium (Ca²⁺+) is maintained by amending the release of parathyroid hormone and through direct effects of the Ca²⁺+ sensing receptor (CaSR) in the renal tubule. Combined, these mechanisms alter intestinal Ca²⁺+ absorption by modulating 1,25-dihydroxy vitamin D₃ production, bone resorption, and renal Ca²⁺+ excretion. The CaSR is a therapeutic target in the treatment of secondary hyperparathyroidism and hypocalcaemia is a common complication seen with calcimimetic therapy. The CaSR is also expressed in intestinal epithelium, however, its role in regulating Ca²⁺+ absorption is unknown. Chronic CaSR activation decreased expression of genes involved in Ca²⁺+ absorption. In Ussing chambers, increasing extracellular Ca²⁺+ or basolateral application of the calcimimetic cinacalcet decreased net Ca²⁺+ absorption across intestinal preparations acutely. Conversely, Ca²⁺+ absorption increased with decreasing extracellular Ca²⁺+ concentration. These responses were absent in mice expressing a non-functional TRPV6, TRPV6^D541A. Cinacalcet also attenuated Ca²⁺+ fluxes through TRPV6 in Xenopus oocytes when coexpressed with the CaSR. Moreover, the phospholipase C inhibitor, U73122, prevented cinacalcetmediated inhibition of Ca²⁺+ flux. These results reveal a regulatory pathway whereby activation of the CaSR in the basolateral membrane of the bowel attenuates Ca²⁺+ absorption via TRPV6 to prevent hypercalcaemia and help to explain how hypocalcaemia is induced by calcimimetics.