Abstract A detailed quantum chemical study of the solvent effects in the intramolecular hydrogen bonding, conformational stability, and reactivity of aspirin has been performed using density functional theory (DFT) at the B3LYP/6‐31G(d) theory level. Seven conformational isomers, three of them presenting intramolecular hydrogen bonds, have been located. Thermochemical functions have been computed, and relative energies and free enthalpies have been determined in gas and aqueous phases. Several molecular properties have been calculated to predict the ability of aspirin to acylate cyclooxygenase (COX) enzymes. A six‐membered‐ring hydrogen‐bonded conformer was found to be the most reactive species. The solvation in aqueous phase increases the reactivity and strengthens intramolecular hydrogen bonding.