Acute poisoning by Organophosphate (OP) pesticides is an essential clinical problem in rural Asia. Crocetin (CRO) and Rutin (RU) are the nucleophile compounds with no toxicity effects. In the present study, the feasibility of crocetin and rutin administration as therapeutic agents for OP poisoning was studied and compared with 2-(pralidoxime) PAM administration in mice. CRO and RU at doses of (50, 100, 200 mg/kg) were administered intraperitoneal (IP) 15 minutes after a single intraperitoneal injection of Diazinon (DIZ) (LD50=366 mg/kg). Atropine (ATR; 20 mg/kg, IP) and pralidoxime (2-PAM; 30 mg/kg, ip) were used alone or together as standard therapy or control in different (12) groups. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were measured after 3 and 24 hours as markers of OP toxicity. Significant increase of AChE and BChE activity was observed by the CRO and RU at all doses as compared with the DIZ group. CRO at the dose of 100 mg/kg and RU at the dose of 200 mg/kg significantly increased the AChE activity and CRO and RU at the dose of 200 mg/kg significantly increased the BChE enzyme activity in comparison to DIZ+PAM and DIZ+ATR after 3 hours. It is concluded that CRO and RUT are more effective than 2-PAM to reactivation and also prevention of re-inhibition of the reactivated enzyme after 3 and 24 hours. High nucleophilic properties of CRO and RU can be considered as the mechanism proposed for AChE reactivation.