Glibenclamide is one of the most prescribed insulin secretagogues in diabetes due to its low cost, but its efficacy on suppressing diabetic complications is limited. Here, we examine whether addition of either vitamin B1 or calcitriol to glibenclamide could produce more suppression of diabetic nephropathy. Type 2 diabetes was induced by high fructose (10 % in drinking water), high salt (3 % in diet), and high fat diet (25 % in diet) for 3 weeks, followed by single dose of STZ (40 mg/kg, i.p.). Diabetic rats were treated with either glibenclamide (0.6 mg/kg), vitamin B1 (70 mg/kg), glibenclamide/vitamin B1, calcitriol (0.1 μg/kg), or glibenclamide/calcitriol. Addition of either vitamin B1 or calcitriol to glibenclamide therapy enabled more suppression of diabetic nephropathy development as evidenced by more preserved creatinine clearance and less renal damage scores. Combination therapy resulted in mild enhancement in the effect of glibenclamide on glucose tolerance without affecting the area under the curve. Combination therapy was associated with more suppression of inflammatory cascades as evidenced by reducing the expression of high mobility group box-1 (HMGB1), toll-like receptor-4 (TLR4), nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α). In addition, combination therapy enhanced the antioxidant mechanisms as evidenced by increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione content and reducing malondialdehyde and nitric oxide levels. Furthermore, combination therapy provided more suppression of fibrotic pathways as appear from reducing collagen deposition and the expression of α- smooth muscle actin (α-SMA). In conclusion, addition of vitamin B1 or calcitriol to glibenclamide therapy can enhance the therapeutic efficiency of glibenclamide in suppressing diabetic nephropathy progression to the same extend, the protective effect is mediated through modulating HMGB1/TLR4/ NF-κB/TNF-α/Nrf2/α-SMA trajectories.