Fibroblast growth factor 23 (FGF23), a hormone required for phosphorus metabolism, was recently proposed to act on Ca2+ uptake; however, the available evidences of how FGF23 controls the body fluid Ca2+ homeostasis needs to be further clarified. The use of zebrafish as a model system revealed that FGF23 is specifically expressed in the corpuscles of Stannius (CS), an organ involved in Ca2+ homeostasis in fish, and its expression is stimulated by ambient water with a high Ca2+ level. The overexpression of FGF23 inhibited Ca2+ uptake by downregulating the mRNA expression of epithelium calcium channel (ECaC). Calcium-sensing receptor (CaSR), which senses changes in extracellular Ca2+ levels and modulates calciotropic hormones in organs controlling Ca2+ homeostasis in vertebrates, was found to be co-expressed with FGF23 in the CS. In addition, upregulated expression of FGF23 mRNA was detected in morphants of stanniocalcin 1 (stc1, another hypocalcemic factor synthesized in the CS), and knockdown of CaSR suppressed such upregulation and enhanced Ca2+ uptake. Taken together, our data indicate that FGF23 functions as a hypocalcemic hormone in zebrafish, and that the CaSR/STC1-FGF23 axis is involved in body fluid Ca2+ homeostasis in vertebrates.