Edible mushrooms, especially Pleurotus spp. contain a wide variety of biomolecules that can play a protective role against oxidative damage. We investigate the effect of formulation of the aqueous extract of three edibles mushrooms commonly consumed in Cameroon on oxidative stress induced in rats induced by lead acetate: Pleurotus pulmonarius, Pleurotus floridanus and Pleurotus sajor-caju. The formulation made of the three species (1w:1w:1w) were dissolved in distilled water for acute toxicity (at 2000 mg/kg of bw) and protective effect (at 400 mg/kg of bw for 21 days) against oxidative stress induced in vivo with lead acetate (35 mg/kg of bw for 3 days). Several parameters were investigated in the serum and organs homogenous such as lipid profile, hepatic and oxidative stress markers. No particular sign of toxicity of the extract were revealed. After lead administration, significant increases were found in serum transaminases activity, creatinine, and lipid profile associated with a decrease of serum protein content and High Density Lipoprotein. In addition, significant increase in lipid peroxidation expressed as the concentration of malondialdehyde (MDA) and decreased level of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) activities in serum, liver and kidney showed oxidative stress due to lead exposure. The pre-treatment with aqueous extract of the mushroom's formulation showed protective effects against lead induced hepato-renal damage by improving antioxidant parameters, as well as ascorbic acid used as a reference. In conclusion, these mushrooms may be used as a natural source of antioxidants for food supplements against oxidative stress.