Increasing the resistance to humid environments is mandatory for the implementation of isoreticular metal-organic frameworks (IRMOFs) in industry. To date, the causes behind the sensitivity of [Zn₄(μ₄-O)(μ-bdc)₃]₈ (IRMOF-1; bdc=1,4-benzenedicarboxylate) to water remain still open. A multiscale scheme that combines Monte Carlo simulations, density functional theory and first-principles Born-Oppenheimer molecular dynamics on IRMOF-1 was employed to unravel the underlying atomistic mechanism responsible for lattice disruption. At very low water contents, H₂O molecules are isolated in the lattice but provoke a dynamic opening of the terephthalic acid, and the lattice collapse occurs at about 6 % water weight at room temperature. The ability of Zn to form fivefold coordination spheres and the increasing basicity of water when forming clusters are responsible for the displacement of the organic linker. The present results pave the way for synthetic challenges with new target linkers that might provide more robust IRMOF structures.