Organophosphate (OP) pesticides are responsible for numerous human deaths every year. Nucleophilic substitution is an important method to mitigate the toxicity of obsolete stocks of OPs. Herein, the degradation of O,O-diethyl-2,4-dinitrophenyl phosphate (DEDNPP) and pesticide diethyl-4-nitrophenyl phosphate (Paraoxon) promoted by 1,2,4-triazole (TAZ) was investigated by means of kinetic studies, nuclear magnetic resonance (NMR) analyses, and theoretical calculations. Results showed fast degradation of OPs is promoted by the anionic form of the nucleophile (TAZ(−)) in pH > 8.5 (optimal at pH = 11). Rate enhancements of 106 and 105-fold in relation to neutral hydrolysis of DEDNPP and Paraoxon were observed, respectively, consistent with alpha-nucleophiles reactivity. TAZ(−) regioselectively promotes the degradation of DEDNPP via P–O bond break, forming a quickly hydrolyzable phosphorylated intermediate, regenerating the nucleophile. Calculations using M06-2X/6-311++G­(d,p) level of theory revealed that the equivalent nitrogen atoms of TAZ(−) are the main nucleophilic center of the molecule. This study expands the knowledge on the reactivity of iminic compounds as detoxificant agents of OPs, indicating the efficiency and selectivity of TAZ(−) in aqueous medium, encouraging the design of novel TAZ-based catalysts.