In several clinical investigations performed in patients with type 2 diabetes mellitus and in diabetic and non-diabetic patients with heart failure or chronic kidney disease, sodium-glucose cotransporter 2 inhibitors (SGLT2i) proved their benefit on cardiac and renal adverse outcomes. Although there is clear evidence regarding the clinical benefits achieved, the pathophysiological mechanisms underlying their efficacy are still poorly understood. Some favorable mechanisms are likely related to the induced glycosuria and natriuresis. Both have been observed since the early stages of the molecule action and can drive beneficial hemodynamic changes, resulting in a decline of glomerular hyperfiltration and activation of the renin-angiotensin-aldosterone system. In addition to the improvement of cardiocirculatory regimen and renal performance, SGLT2i have an important role in cardio-renal protection by improving the metabolism of cardiomyocytes, carrying out anti-fibrotic and anti-inflammatory action and increasing the expression of cardio-protective adipokines. Further studies are needed to better understand the molecular mechanisms underlying the favorable effects of these drugs in diabetic and non-diabetic patients. The purpose of this review article is to analyze the molecular mechanisms underlying the cardiovascular benefits of SGLT2i in each of the main organs involved in the cardio-renal axis. Furthermore, the manuscript aims to analyze the extent of the beneficial effects of SGLT2i on heart failure in the different populations investigated in the most recent clinical studies.