The heterogeneous liquid–liquid O-glycosidation is a crucial step in pharmaceutical synthesis. Herein, a theoretical methodology based on COSMO-RS, quantum chemical calculations combined with Transformer-CNN model was used to screen ionic liquids (ILs) as phase transfer catalysts (PTCs) to intensify O-glycosidation between 4-nitrophenol and 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide. The anions of ILs were screened by the evaluation of ILs hydrophilicity via infinite dilution selectivity of ILs and the molecular descriptor HB_acc3 of the anion using COSMO-RS, a predictive model for thermodynamic properties. Additionally, the binding energy between the phenoxide anion and IL cation was used to assess reaction extent in the aqueous phase through quantum chemical calculation. The cations of ILs were evaluated by the infinite dilution selectivity of the combination between phenoxide anion and IL cations, and physical properties including viscosity and melting point were also predicted using an advanced Transformer-CNN model. The screened IL 1-octyl-3-methylimidazolium acetate and 1-hexyl-3-methylimidazolium acetate were demonstrated its superior catalytic activity for the aromatic O-glycosidation of not only 4-nitrophenol, but also various phenols and thiophenols. Moreover, the presence of PTCs enhances the likelihood of the reactant migrating into another phase. This behavior is validated by COSMO-RS calculated liquid–liquid equilibrium (LLE) and interaction energy analysis. The method provides great potential for screening and designing ILs as phase transfer catalysts for heterogeneous liquid–liquid reactions.