Owing to their high surface area, high concentration of active metal sites, and water stability,z irconium(VI)based metal-organic frameworks (Zr-MOFs) have shown excellent activity in the hydrolysis of organophosphorus nerve agents (OPNs). In this regard, for the first time, two topologically different Zr-MOFs (Zr-fcu-tmuc andZ r-bcu-tmuc, constructed from the same organic and inorganic building blocks;f cu = face-centered cubic, bcu = body-centered cubic) have been rationally chosen to investigate the effect of network topology on the catalytic hydrolysis of the nerve agent simulant,d imethyl 4-nitrophenylp hosphate (DMNP). Ar emarkable enhancement in the hydrolysis rate of DMNP was observed with Zr-bcu-tmuc, reducing the half-life more than threefold compared with Zr-fcu-tmuc. Greater accessibility of the active Zr VI sites in the 8-connectedb cu net compared with the 12-connected fcu leads to af aster hydrolysis of DMNP on Zr-bcu-tmuc. Interestingly,t he higher activity of Zr-bcu-tmuc was also confirmed by its higher fluorescence sensitivity towards DMNP (limit of detection (LOD) = 0.557 mm)c ompared with Zr-fcu-tmuc (LOD = 1.09 mm). The resultss how that controlling the desired topologyo fZ r-MOFs is au seful strategyf or improving their performance in the detection and catalytic detoxificationofO PNs.