Vancomycin-nephrotoxicity has been reported to occur in 5–25% of patients who were administered with it. Several natural antioxidants were found to be effective against drug induced toxicity. We evaluated the possible protective effects of spirulina and pycnogenol alone or in combination on vancomycin induced renal cortical oxidative stress. Forty nine rats were randomly divided into seven groups named: group I; control, group II; received spirulina 1000 mg/kg/day, group III; received pycnogenol 200 mg/kg/day, group IV; received vancomycin 200 mg/kg/day every 12 hours, group V; (spirulina + vancomycin), group VI; (pycnogenol + vancomycin) and group VII; (pycnogenol + spirulina + vancomycin). At the end of the experiment, kidney functions were estimated and then the kidneys were removed, weighed and sampled for histopathological, immunohistochemistry and biochemical studies. Administration of spirulina and pycnogenol alone or in combination decreased elevated serum creatinine, blood urea nitrogen, renal malondialdehyde and immunoexpression of the proapoptotic protein (Bax), autophagic marker protein (LC3/B) and inducible nitric oxide synthase induced by vancomycin. They increased reduced glutathione, glutathione peroxidase, superoxide dismutase and immunoexpression of the antiapoptotic protein (Bcl2). They also ameliorated the morphological changes induced by vancomycin. The combination therapy of spirulina and pycnogenol showed better protective effects than the corresponding monotherapy.