Diabetic nephropathy (DN) is the main cause of end stage renal disease. Complex mechanisms are implicated in the pathogenesis of DN including the accumulation of advanced glycation end products (AGEs), oxidative stress, and inflammation mediated through the upregulation of toll-like receptor 4 (TLR4). Hibiscus sabdariffa is widely used in food products possessing anti-oxidative, anti-inflammatory, anti-diabetic, and anti-hypertensive effects. The present study aimed to investigate the role of hibiscus extract against streptozotocin(STZ)-induced DN compared to lisinopril, and to evaluate the effects of their combined administration. Rats were treated with hibiscus extract (100, 200, or 400 mg/kg), lisinopril (5 mg/kg), or lisinopril plus hibiscus extract (2.5/100 mg/kg) for 8 weeks. Hibiscus extract caused a dose-dependent improvement of nephropathy, and suppressed oxidative stress, inflammation, and the upregulation of TLR4 induced by STZ. The effects of hibiscus extract (400 mg/kg) were comparable to lisinopril (5 mg/kg). Interestingly, the combined administration of lisinopril plus hibiscus extract (2.5/100 mg/kg) significantly improved the manifestations of nephropathy better than lisinopril or hibiscus extract alone. These results might support the application of hibiscus extract as an alternative to the conventional angiotensin-converting enzyme inhibitors (ACEIs) or at least as an adjunctive to augment their effects in DN.