Diabetes mellitus is a risk factor for muscle loss and sarcopenia. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) or “gliflozins” are one of the newest anti-hyperglycemic drugs. They reduce blood glucose levels by inhibiting renal glucose reabsorption in the early proximal convoluted tubule. Various randomized trials showed that SGLT2i have cardio-protective and reno-protective action. SGLT2i also affect body composition. They usually decrease body fat percentage, visceral and subcutaneous adipose tissue. However, regarding the muscle mass, there are conflicting findings some studies showing detrimental effects and others showed neutral or beneficial effects. This issue is extremely important not only because of the wide use of SGLT2i around globe; but also skeletal muscle mass consumes large amounts of calories during exercise and is an important determinant of resting metabolic rate and skeletal muscle loss hinders energy consumption leading to obesity. In this systematic review, we extensively reviewed the experimental and clinical studies regarding the impact of SGLT2i on muscle mass and related metabolic alterations. Importantly, studies are heterogeneous and there is unmet need to highlight the alterations in muscle during SGLT2i use.