Early detection and clinical interference are major challenges for the prevention of diabetic nephropathy (DN) progression. This study investigated the effects of dapagliflozin, a sodium glucose co-transporter 2 inhibitor, on some early markers for DN in fructose-streptozotocin (Fr-STZ)-induced diabetes in rats. Fr-STZ rats were treated with either dapagliflozin (1 mg/kg p.o. daily), metformin (350 mg/kg p.o. daily), or their combination for 6 weeks. Fr-STZ rats displayed marked early tubular renal damage and glomerular podocyte injury as evidenced by renal KIM-1, NGAL, cystatin C, and vanin-1 mRNA, as well as urinary NAG elevation and nephrin mRNA suppression, associated with the development of marked renal interstitial fibrosis and glomerulosclerosis despite the presence of normoalbuminuria. Propagation of oxidative, inflammatory, fibrotic, and apoptotic reactions was obvious in the setting of renal glucose overload. Dapagliflozin significantly attenuated the renal tubular injury makers namely KIM-1, NGAL, vanin-1 and urinary NAG. In addition, it restored glomerular nephrin expression and reversed renal histopathological changes. Oxidative, inflammatory, and fibrotic processes were also alleviated. This study suggests that dapagliflozin exerts a renoprotective effect against early features of DN in rats presumably by inhibition of diabetes-induced renal tubular and glomerular injury thereby modulating oxidative, inflammatory, and fibrotic as well as apoptotic mechanisms elicited during hyperglycemia.