The water‐exchange mechanism of [UO2(OH2)5]2+ has been reinvestigated by using ab initio molecular orbital (MO) methods. The geometries and the vibrational frequencies were computed with CAS‐SCF(12/11)‐SCRF and CAS‐SCF(12/11)‐PCM methods, which take into account static electron correlation (using the complete active space self‐consistent field (CAS‐SCF) technique, based on an active space of 12 electrons in 11 orbitals) and hydration (using the self‐consistent reaction field (SCRF) and polarizable continuum model (PCM) techniques). The total energies were computed with multiconfiguration quasi‐degenerate second‐order perturbation theory, the MCQDPT2(12/11)‐PCM method, which treats static and dynamic electron correlation as well as hydration. The adequacies of other currently used quantum chemical methods, MP2, CCSD(T), B3 LYP, and BLYP, are discussed. For the associative and dissociative pathways, thermodynamic activation parameters (ΔH ≠, ΔS ≠, and ΔG ≠) were computed. For the associative mechanism, the calculated ΔH ≠ and ΔG ≠ values agree with experiment, whereas for the dissociative mechanism, they are higher by ≈20 kJ mol−1. The dissociative mechanism is preferred for substitution reactions of uranyl(VI) complexes with ligands that are stronger electron donors than water. The question of whether a concerted (Ia or Id) or a stepwise (A or D) mechanism operates is discussed on the basis of the computed lifetime of the respective intermediate, and the duration of the vibration with which the intermediate is transformed into the product.