Malathion is an organophosphorus pesticide widely used throughout agriculture and veterinary practices. The present study aimed to evaluate the toxic effects of Malathion inhalation through simulation of three models of environmental toxicity in different exposure periods of acute, chronic, and subchronic doses. The histological, immunohistochemical examinations of the morphological integrity of the liver and brain, together with some biochemical (TAC, CAT, SOD, GPx and Se) and molecular (Real-time PCR for p53 and P21 mRNA) studies will be assessed to highlight the effects of the studied sub-lethal doses of Malathion. Four groups of male Wister rats were used in the experiment one for the control group and the others for subchronic, chronic and acute doses. Many toxic symptoms, a significant decrease in CAT, CAT, SOD, GPx and Se values. Malathion cause also significant disturbance in different comet assay parameters in both blood and liver tissue cells. Also, Real-time PCR for mRNA of P53 and P21 in the liver showed a significant increase in mRNA expression of P53 and P21 and a significant decrease in mRNA expression of P53 and P21 in brain tissue. P53 immunohistochemistry in liver tissue shows an increase in its activity and a decrease in hippocampus tissue cells. Many histopathological lesions such as inflammation, vacuolation, apoptosis, necrosis, and fibrosis of the hepatic tissue cells, were recorded in all treated groups.