This work established a binary ionic liquid-solvent system for effective enzymatic esterification of naturally occurring phenolic glycosides (flavonoids); which could result in a dramatic enhancement of Novozym 435-catalyzed esterification of esculin, demonstrating a great synergetic effect. In essence, [OMIM][BF4]-toluene and [TOMA][Tf2N]-hexane binary systems both served >90 mol% of conversions of esculin after 96 h of reaction at 60 °C. Typically, binary [TOMA][Tf2N]-hexane system enabled Novozym 435 with extremely high catalytic efficiency (kcat/Km = 17.57 × 10-2 (Ms)-1), which was 55-fold higher than that Novozym 435 exhibited in t-butanol solvent (one of the best solvent systems for esterification reactions). It was also found that the superiormatching in property and structure between IL and solvent was the decisive factor for the outperformance of [TOMA][Tf2N]-hexane binary system, in which [TOMA] and hexane facilitate the solubilization of esculin and fatty acids and [Tf2N]- anions and hexane offer protective effects for lipase at elevated temperatures.