Key points The cortical collecting duct (CCD) plays an essential role in sodium homeostasis by fine‐tuning the amount of sodium that is excreted in the urine. Ex vivo, the microperfused CCD reabsorbs sodium in the absence of lumen‐to‐bath concentration gradients. In the present study, we show that, in the presence of physiological lumen‐to‐bath concentration gradients, and in the absence of endocrine, paracrine and neural regulation, the mouse CCD secretes sodium, which represents a paradigm shift. This secretion occurs via the paracellular route, as well as a transcellular pathway that is energized by apical H+/K+‐ATPase type 2 pumps operating as Na+/K+ exchangers. The newly identified transcellular secretory pathway represents a physiological target for the regulation of sodium handling and for anti‐hypertensive therapeutic agents. Abstract In vitro microperfusion experiments have demonstrated that cortical collecting ducts (CCDs) reabsorb sodium via principal and type B intercalated cells under sodium‐depleted conditions and thereby contribute to sodium and blood pressure homeostasis. However, these experiments were performed in the absence of the transepithelial ion concentration gradients that prevail in vivo and determine paracellular transport. The present study aimed to characterize Na+, K+ and Cl− fluxes in the mouse CCD in the presence of physiological transepithelial concentration gradients. For this purpose, we combined in vitro measurements of ion fluxes across microperfused CCDs of sodium‐depleted mice with the predictions of a mathematical model. When NaCl transport was inhibited in all cells, CCDs secreted Na+ and reabsorbed K+; Cl− transport was negligible. Removing inhibitors of type A and B intercalated cells increased Na+ secretion in wild‐type (WT) mice but not in H+/K+‐ATPase type 2 (HKA2) knockout mice. Further inhibition of basolateral NaCl entry via the Na+‐K+‐2Cl− cotransporter in type A intercalated cells reduced Na+ secretion in WT mice to the levels observed in HKA2−/− mice. With no inhibitors, WT mouse CCDs still secreted Na+ and reabsorbed K+. In vivo, HKA2−/− mice excreted less Na+ than WT mice after switching to a high‐salt diet. Taken together, our results indicate that type A intercalated cells secrete Na+ via basolateral Na+‐K+‐2Cl− cotransporters in tandem with apical HKA2 pumps. They also suggest that the CCD can mediate overall Na+ secretion, and that its ability to reabsorb NaCl in vivo depends on the presence of acute regulatory factors.