Enzyme activity in organic solvents is usually much lower than its performance in aqueous media. To develop water-mimicking environment for the enzyme, we designed ionic liquids functionalized with tert-alcohol (as hydrogen-bond donor) and ether groups (as hydrogen-bond acceptors). These “water-like” ionic media have high thermal stability and low viscosities, and produced higher lipase and protease activities and stabilities than some enzyme-compatible organic solvents (such as tert-butanol and diisopropyl ether) and conventional ionic liquids (e.g., [BMIM][Tf₂N]) during transesterification reactions under low water contents. In addition, these unique ionic solvents are found suitable media for asymmetric synthesis. Our experimental and MD simulations data illustrate the interactions between these water-mimicking solvent molecules and the enzyme.