The objective of this study was to examine theoretically how Ca ²⁺ reabsorption in the proximal tubule (PT) is modulated by Na ⁺ and water fluxes, parathyroid hormone (PTH), Na ⁺ -glucose cotransporter (SGLT2) inhibitors, and acetazolamide. We expanded a previously published mathematical model of water and solute transport in the rat PT (Layton AT, Vallon V, Edwards A. Am J Physiol Renal Physiol 308: F1343-F1357, 2015) that did not include Ca ²⁺ . Our results indicate that Ca ²⁺ reabsorption in the PT is primarily driven by the transepithelial Ca ²⁺ concentration gradient that stems from water reabsorption, which is itself coupled to Na ⁺ reabsorption. Simulated variations in permeability or transporter activity elicit opposite changes in paracellular and transcellular Ca ²⁺ fluxes, whereas a simulated decrease in filtration rate lowers both fluxes. The model predicts that PTH-mediated inhibition of the apical Na ⁺ /H ⁺ exchanger NHE3 reduces Na ⁺ and Ca ²⁺ transport to a similar extent. It also suggests that acetazolamide- and SGLT2 inhibitor-induced calciuria at least partly stems from reduced Ca ²⁺ reabsorption in the PT. In addition, backleak of phosphate (PO ₄ ) across tight junctions is predicted to reduce net PO ₄ reabsorption by ~20% under normal conditions. When transcellular PO ₄ transport is substantially reduced by PTH, paracellular PO ₄ flux is reversed and contributes significantly to PO ₄ reabsorption. Furthermore, PTH is predicted to exert an indirect impact on PO ₄ reabsorption via its inhibitory action on NHE3. This model thus provides greater insight into the mechanisms that modulate Ca ²⁺ and PO ₄ reabsorption in the PT.