The biodegradation of organophosphorus compounds (OPs) by phosphotriesterase (PTE) is an efficient and eco-friendly way. However, the low catalytic activity and instability of PTE becomes the key limiting step for the practical application. In this study, a new multimetal-based organic–inorganic self-assembly hybrid system was proposed to ameliorate this situation. A series of characterization methods demonstrated that the synthesized multimetallic PTE hybrid complex (Co/MnHF@PTE) exhibited a hierarchical flower-like structure. The activity recovery and the effective encapsulation yield of the Co/MnHF@PTE was 408% and 84.5%, respectively. The kcat/Km of Co/MnHF@PTE was separately 2.9-, 1.3-, and 2.7-fold higher than MnHF@PTE, CoHF@PTE, and free PTE. The hybrid nanoflowers showed preferable durability, stability, and reusability. When Co/MnHF@PTE was applied in a pump-flow reactor, the degradation percent of methyl parathion could be maintained at more than 93% with the injection of 24 ml of reaction mixture. More importantly, the Co/MnHF@PTE can effectively break P-F or P-S bond of soman (GD) and nerve agent VX to produce non-toxic products through hydroxyl nucleophilic attack. This study provides a feasible method to improve the activity and stability of PTE, promoting the biodegradation of OPs in the environment.