GNAS, which encodes the stimulatory G protein (heterotrimeric guanine nucleotide–binding protein) α subunit (Gα_s), also encodes a large variant of Gα_s termed extra-large α subunit (XLα_s), and alterations in XLα_s abundance or activity are implicated in various human disorders. Although XLα_s, like Gα_s, stimulates generation of the second messenger cyclic adenosine monophosphate (cAMP), evidence suggests that XLα_s and Gα_s have opposing effects in vivo. We investigated the role of XLα_s in mediating signaling by parathyroid hormone (PTH), which activates a G protein–coupled receptor (GPCR) that stimulates both Gα_s and Gα_q/11 in renal proximal tubules to maintain phosphate and vitamin D homeostasis. At postnatal day 2 (P2), XLα_s knockout (XLKO) mice exhibited hyperphosphatemia, hypocalcemia, and increased serum concentrations of PTH and 1,25-dihydroxyvitamin D. The ability of PTH to reduce serum phosphate concentrations was impaired, and the abundance of the sodium phosphate cotransporter Npt2a in renal brush border membranes was reduced in XLKO mice, whereas PTH-induced cAMP excretion in the urine was modestly increased. Basal and PTH-stimulated production of inositol 1,4,5-trisphosphate (IP₃), which is the second messenger produced by Gα_q/11 signaling, was repressed in renal proximal tubules from XLKO mice. Crossing of XLKO mice with mice overexpressing XLα_s specifically in renal proximal tubules rescued the phenotype of the XLKO mice. Overexpression of XLα_s in HEK 293 cells enhanced IP₃ generation in unstimulated cells and in cells stimulated with PTH or thrombin, which acts through a G_q/11-coupled receptor. Together, our findings suggest that XLα_s enhances G_q/11 signaling to mediate the renal actions of PTH during early postnatal development.