The health hazardous occurred in both human and animals as a result of the continuous misuse of pesticides drives the researchers for looking about the solution. Natural plant extracts contain active phyto-constituents with antioxidant potency enables them to inhibit production of the free radicals that induce damage of the cells. The present study aimed to reveal efficiency of Saussurea costus (S. costus) extract against the hepato- and neurotoxicity induced by Chloropyrifos ethyl (CPF) in experimental animals (rats). The gas chromatography / mass spectrometer (GC/MS) that used for analyzing the active constituents in S. costus extract showed that the extract contains 11 potent active compounds and Dehydrocostuslactone represents about 77.37% and considered as the most dominant compound in the extract. Both of CPF and S. costus extract were studied on the rats that were divided into 6 groups as the following: Group 1 (control) received distilled water orally. Groups 2&3 (S. costus extract treated groups) received S. costus extract orally at a dose of 0.25 and 0.50 ml, respectively. Group 4 (CPF injected group) was injected with CPF at a dose of 3 mg/kg.bw. Groups 5&6 (CPF + S. costus extract group) injected with CPF then treated with S. costus extract at two tested doses respectively. The most hematological and biochemical measurements declined significantly (P≤0.05) in CPF injected group. S. costus extract restored all tested parameters towards the control values. Moreover, the electrophoretic isoenzyme showed that the physiological alterations occurred in the esterases (ESTs) as a result of CPF injection were represented by hiding normal EST types associated with existence of abnormal ones. Therefore, the similarity index (SI%) and genetic distance (GD%) values were altered with α-EST (SI=80.00%; GD=20.00%) and β-EST (SI=50.00%; GD=50.00%) patterns in CPF injected group. The S. costus extract at a dose of 0.5 ml restored integrity of these isoenzymes pattern by restoring the absent types with hiding the abnormal ones. Therefore, this group became physiologically similar to control group (SI=100.00%; GD=0.00%). These results were supported by histopathological examination for the target organs (brain, liver and kidney) that were affected by CPF and the S. costus extract improved architecture of these organs and restored their histopathological integrity to normal structure.