Metal–organic polyhedra (MOPs) are discrete molecules made of metal ions/clusters and organic ligands, and their crystal packing leads to the generation of intrinsic and extrinsic porosity. Due to their structural versatility, porosity, and nanoscale size, MOPs are considered an attractive platform for catalysis. In this study, we report for the first time the use of three zirconium(IV)-based MOPs for the degradation of trace concentrations of the nerve agent simulant, dimethyl 4-nitrophenyl phosphate (DMNP). All three MOPs degraded DMNP instantaneously, with half-lives ranging from t_1/2 = 17 to 130 s. The catalytic activity of MOPs is thought to be due to (1) their periodic packing resulting in long-range order that creates extrinsic porosity, allowing DMNP to diffuse in and interact with the pore surface and Lewis acids (Zr(IV) centers) of MOPs, and (2) the lability of the Zr–Cp⁻ (Cp⁻ = cyclopentadienyl) bond, allowing Cp⁻ ligands to rearrange and make space for DMNP to interact with the Zr(IV). The catalytic activity of MOPs is not deteriorated by increasing the concentration of the nerve agent simulant nor in consecutive catalytic experiments, highlighting their robustness as catalysts. Our study showcases the promise of MOPs as one of the fastest active catalysts for the instantaneous degradation of nerve agents.