Dexamethasone (DEX) can exert a cytotoxic effect on cultured osteoblasts. The current study explored the potential osteoblast cytoprotective effect of fibroblast growth factor 23 (FGF23). In OB-6 human osteoblastic cells and primary murine osteoblasts, FGF23 induced phosphorylation of the receptor FGFR1 and activated the downstream Akt-S6K1 signaling. FGF23-induced FGFR1-Akt-S6K phosphorylation was largely inhibited by FGFR1 shRNA, but augmented with ectopic FGFR1 expression in OB-6 cells. FGF23 attenuated DEX-induced death and apoptosis in OB-6 cells and murine osteoblasts. Its cytoprotective effects were abolished by FGFR1 shRNA, Akt inhibition or Akt1 knockout. Conversely, forced activation of Akt inhibited DEX-induced cytotoxicity in OB-6 cells. Furthermore, FGF23 activated Akt downstream nuclear-factor-E2-related factor 2 (Nrf2) signaling to alleviate DEX-induced oxidative injury. On the contrary, Nrf2 shRNA or knockout almost reversed FGF23-induced osteoblast cytoprotection against DEX. Collectively, FGF23 activates FGFR1-Akt and Nrf2 signaling cascades to protect osteoblasts from DEX-induced oxidative injury and cell death.