Zr-based metal-organic frameworks (MOFs) have been known for their excellent stability; however, due to the high connectivity of the Zr-6 nodes, it is challenging to introduce flexibility into Zr-MOFs. Here we present a flexible Zr-MOF named NU-1400 comprising 4-connected Zr-6 nodes and tetratopic linkers. It exhibits guest-dependent structural flexibility with up to 48% contraction in the unit cell volume as evidenced by single-crystal X-ray diffraction studies. The expanded or contracted conformations of NU-1400 showed drastically different reactivity toward the hydrolysis of a nerve agent simulant owing to the size-selective effect toward the reactant.