The traditional chemical isomerization of lactose into lactulose faces unfavorable thermodynamic limitations, significant side reactions, and high purification cost challenges. Herein, an efficient strategy for combining extraction-assisted isomerization and simultaneous purification of lactulose is presented. Under optimized conditions, 4-vinylphenylboronic acid (VPBA) favored the selective extraction of lactulose and up to 80% of lactulose can be extracted with a high selectivity (>95%). The extracted lactulose can be rapidly (<10 min) back-extracted into an acidic HCl solution as a concentrated lactulose stream (∼20 g/L). Lactulose purity can significantly be improved to 99.64% through a two-staged stripping process as a function of HCl contents. In situ removal of the newly formed lactulose catalyzed by Na 2 HPO 4 + NaOH through selective extraction could significantly promote lactulose yield and minimize the formation of byproducts. The applied extraction-assisted isomerization strategy enabled the yield of lactulose up to ∼70% (batch-extraction model) and ∼85% (in situ extraction model), with the lowest yield of byproducts (<5%) ever found. Remarkably, the VPBA-dominated organic phase and the catalyst-containing aqueous phase could be easily regenerated and reused multiple times, well proving their feasibility in clean and sustainable industrial applications. This trial validates for the first time the use of the extraction-assisted strategy for an effective simultaneous isomerization and isolation of high-purity lactulose.