DFT calculations have been conducted to gain insight into the mechanism and kinetics of the esterification of α-tocopherol with succinic anhydride catalyzed by a histidine derivative or an imidazolium-based ionic liquid (IL). The two catalytic reactions involve an intrinsically consistent molecular mechanism: a rate-determining, concerted nucleophilic substitution followed by a facile proton-transfer process. The histidine derivative or the IL anion is shown to play a decisive role, acting as a Brönsted base by abstracting the hydroxyl proton of α-tocopherol to favor the nucleophilic substitution of the hydroxyl oxygen of α-tocopherol on succinic anhydride. The calculated free energy barriers of two reactions (15.8 kcal/mol for the histamine-catalyzed reaction and 22.9 kcal/mol for the IL-catalyzed reaction) together with their respective characteristic features, the catalytic reaction with a catalytic amount of histamine vs the catalytic reaction with an excessed amount of the IL, rationalize well the experimentally observed kinetics that the former has faster initial rate but longer reaction time while the latter is initiated slowly but completed in a much shorter time.