The mechanism of renal toxicity after exposure to pesticides is not completed known until now. Some scientists suggested that the accumulation of pesticide residues in kidney tissue is one theory for explaining how pesticides alter kidney function and cause cell injury. This study is, therefore, the first one to explain the mechanism of pirimiphos-methyl (PM) induce kidney dysfunction and damage in mice. The ameliorative effect of Origanum majorana leaves extract against renal dysfunction and damage. The effect of pirimiphos-methyl (PM) on gene expression, DNA damage, oxidant/antioxidant status and renal toxicity of male mice were studied. Chemical fingerprint by HPLC and GC/MS of O. majorana leave extract and their ameliorative role was investigated. Mice received PM orally at dose 12.0 mg/kg b. wt. (1/10 LD50) for four weeks with or without plant extracts at dose 150 and 300 mg/kg. b. wt. Phenolic and flavonoid compounds e.g., gallic acid, protocatechuic and cateachin while beta-terpineol (25.71%), gamma-terpineol (15.03%), (-)-spathulenol (10.79%), terpinen-4-ol (10.59%), terpineol (10.08%) and trans-caryophyllene by GC-MS analysis. Pirimiphos methyl increased molecule-1 gene (KIM-1) relative expression and increased percentage of the cell with DNA damage in kidney tissue of mice. It changed antioxidant biomarkers such as glutathione-s-transferees (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and lipid peroxidation (LPO) in the kidney. They enhanced the concentration of uric acid and creatinine in serum and caused histopathological alterations in the kidney tissue. Co-administration of plant extract restored serum kidney function and oxidative stress biomarkers within the normal range especially at a high dose of plant extracts. It can be concluded that the mechanism of renal damage induced by PM could be due to the effect on molecule-1 gene (KIM-1) expression and damage DNA in the renal cells. The mechanism of change in kidney function and injure could be due to the imbalance between oxidant/antioxidant status because of producing reactive oxygen species. Administration of O. majorana extract ameliorates KIM-1 gene expiration, reduced DNA damage, and improved kidney function and protect renal cells via their scavenger ability to free radicals. These findings indicated that leave extract of O. majorana could be used as a tea to protect agricultural workers and pesticide sprayers against oxidative damage and kidney injury induced by pesticides. Key words: Gene expression, DNA, Comet assay, pirimiphos-methyl, oxidative stress, HPLC, GC-MS, Origanum majorana, kidney, mice.