The nerve agent VX is among the most toxic chemicals known to mankind, and robust solutions are needed to rapidly and selectively deactivate it. Herein, we demonstrate that three Zr₆-based metal–organic frameworks (MOFs), namely, UiO-67, UiO-67-NH₂, and UiO-67-N(Me)₂, are selective and highly active catalysts for the hydrolysis of VX. Utilizing UiO-67, UiO-67-NH₂, and UiO-67-N(Me)₂ in a pH 10 buffered solution of N-ethylmorpholine, selective hydrolysis of the P–S bond in VX was observed. In addition, UiO-67-N(Me)₂ was found to catalyze VX hydrolysis with an initial half-life of 1.8 min. This half-life is nearly 3 orders of magnitude shorter than that of the only other MOF tested to date for hydrolysis of VX and rivals the activity of the best nonenzymatic materials. Hydrolysis utilizing Zr-based MOFs is also selective and facile in the absence of pH 10 buffer (just water) and for the destruction of the toxic byproduct EA-2192.