Sodium-glucose transporter 2 (SGLT2) carries glucose across apical membranes of polarized epithelial cells against concentration gradients, driven by Na+ gradients. SGLT2 is mainly expressed in the kidney and responsible for most glucose reabsorption in the convoluted proximal tubules. SGLT2 inhibitors are widely used as anti-diabetic drugs. Recently, SGLT2 inhibitors significantly reduce cardiovascular events in humans with T2D; however, the underlying mechanism remains unclear. Here, we demonstrated that SGLT2 inhibition can increase systemic and tissue levels of beta-hydroxybutyrate (BHB), one of the ketone metabolites. In both normal and diabetic mice, SGLT2i increased tissue beta-hydroxybutyrate (BHB) contents in liver, intestine and kidney as well as in serum and urine. In these organs, SGLT2i upregulated the mRNA expressions of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) and 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMGCL). Similar patterns were observed in kidney for the protein expression of sodium-dependent monocarboxylate transporters (SMCT), which mediate the cellular uptake of BHB and butyrate. SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney and intestine, suggesting the integrated physiological consequences for ketone body metabolism of SGLT2i administration.