Sodium glucose co-transporter 2 inhibitors (SGLT-2i’s) significantly improve cardiovascular outcome in both diabetic and non-diabetic patients. Preclinical studies suggest that SGLT-2i’s directly affect endothelial function in a glucose-independent manner. The effects of SGLT-2i’s include reduction of oxidative stress and inflammatory reaction in endothelial cells. Furthermore, SGLT2i’s have been shown to restore endothelial-related vasodilation and to regulate angiogenesis. The favorable cardiovascular effects of SGLT-2i’s might be mediated via multiple pathways: 1) by inhibition of the overactive sodium-hydrogen exchanger; 2) by reduction of nicotinamide adenine dinucleotide phosphate oxidases expression; 3) by alleviation of mitochondrial injury; 4) by the suppression of inflammatory-related signaling pathways (e.g. by affecting nuclear factor kappa beta); 5) by modulation of glycolysis, as well as 6) by restoring impaired nitric oxide bioavailability. This review focuses on the most recent progress and existing gaps in preclinical investigations concerning the direct effects of SGLT-2i’s on endothelial dysfunction and their underlying mechanisms.