Pesticides are widespread synthesized substances used for public health protection and agricultural programs. However, they cause environmental pollution and health hazards. This study aimed to examine the protective effects of sesame oil (SO) on the genetic alterations induced by cypermethrin (CYP) in the liver and kidney of Wistar rats. Male rats were divided into four groups, each containing 10 rats; the control group received vehicle; SO group (5 mL/kg b.w); CYP group (12 mg/kg b.w), and protective group received SO (5 mL/kg b.w) plus CYP (12 mg/kg b.w). Biochemical analysis showed an increase in albumin, urea, creatinine, GPT, GOT and lipid profiles in CYP group. Co-administration of SO with CYP normalized such biochemical changes. CYP administration decreased both the activity and mRNA expression of the examined antioxidants. SO co-administration recovered CYP down regulate the expression of glutathione-S-transferase (GST), catalase and superoxide dismutase. Additionally, SO co-administration with CYP counteracted the CYP- altered the expression of renal interleukins (IL-1 and IL-6), tumor necrosis factor alpha (TNF-), heme oxygenase-1 (HO-1), anigotensinogen (AGT), AGT receptors (AT1) and genes of hepatic glucose and fatty acids metabolism. CYP induced degenerative changes in the kidney and liver histology which are ameliorated by SO. In conclusion, SO has a protective effect against alterations and pathological changes induced by CYP in the liver and kidney at genetic and histological levels.