Diabetes is the most prevalent disorder in the world characterized by uncontrolled high blood glucose levels and nephropathy is one of the chief complications allied with hyperglycemia. Vanillic acid; the main bioactive compound derived from natural sources such as vegetables, fruits and plants possesses various pharmacological activities such as antioxidant, anti-inflammatory and anti-proliferative. The current study was designed to investigate the antidiabetic and renoprotective effects of vanillic acid by its various pharmacological activities. Streptozotocin (50 mg/kg)/nicotinamide (110 mg/kg) was used to induce diabetes in rats. Oral administration of vanillic acid once daily for 6 weeks (25, 50 and 100 mg/kg) significantly reduced the hyperglycemia, increased liver enzymes and normalized lipid profile that was altered in diabetic rats. Moreover, vanillic acid attenuated the impaired renal function as evidenced by a reduction in serum creatinine, urea, uric acid and urinary microproteinuria levels with a concomitant increase in urinary creatinine clearance in the nephropathic rats. Diabetic rats showed a marked increase in thiobarbituric acid reactive substances (TBARS) and superoxide anion generation (SAG) along with decreased reduced glutathione (GSH) in the renal tissue which was ameliorated in the vanillic acid-treated rats. Histopathologically, vanillic acid treatment was associated with reduced damage with normalized structural changes in renal tissue. Furthermore, treatment groups showed the suppression of upregulation of nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, cyclo-oxygenase (COX)-2 and up-regulation of Nuclear factor-erythroid 2-related factor 2 (Nrf-2) in the renal tissue. In conclusion, vanillic acid's ameliorative impact on diabetic nephropathic rats may be attributed to its powerful free radical scavenging property, down-regulation of NF-κB, TNF-α, COX-2 and up-regulation of Nrf-2 proteins in renal tissue.