Abstract The reaction mechanism between 2,4-diisocyanatotoluene (2,4-TDI) and water clusters was carried out using density functional theory (DFT) at the B3LYP/6-311++G(d,p) level. The reaction can occur via two pathways. In path a, the 2,4-TDI reacts with water molecules by the attack across the N=C bond to form carbamic acid further decomposed into carbon dioxide and amine. In path b, the hydrolysis proceeds with the attack across C=O bond followed by a 1,3-hydrogen shift to produce carbamic acid. The calculations indicated that the additions across N=C and C=O bonds with water trimer are energetically preferred to the reaction with water dimer and monomer with the free energy barrier of 22.9 and 27.0 kcal mol−1 respectively, which is consistent with the experimental results that the pseudo-first-order rate constants of the reaction are dependent on [H2O]3. In addition, the 1,3-hydrogen shift following an attack across C=O bond is a fast process with water dimer serving as an efficient proton transporter resulting in the free energy barrier of 5.4 kcal mol−1. In the final decomposition of carbamic acid, water trimer or water tetramer shows an important role with the free energy barrier of 16.4 and 15.3 kcal mol−1 respectively. The results show that the 4-position isocyanate group of 2,4-TDI is more active than that of 2-position.