Direct upgrading of the biomass-derived sorbitol platform to high-value isosorbide esters is important for efficient utilization of the biomass polyhydroxyl structure, but it is challenging owing to the tandem nature of the reaction and severe side reactions such as isomerization and humin formation. Here we report a simple and efficient approach for the selective direct conversion of sorbitol in fatty acids to isosorbide esters over H-beta zeolite by utilizing methyl isobutyl ketone (MIBK). The key to the success of this tandem reaction is the introduction of MIBK to control the reaction pathway and minimize the side reactions. The reactive terminal vicinal-diol group on sorbitol and the 1,4-sorbitan intermediate is first stabilized by MIBK via preferential ketalization, forming the 1,3-dioxolane structure. This terminal five-membered ketal ring can both promote the dehydration of sorbitol to isosorbide resulting in controlling the cascade sequence of sorbitol dehydration–esterification and prevent the side reactions of sorbitol and 1,4-sorbitan. In addition, MIBK stabilizes the esterification derivatization of the isosorbide intermediate, completely inhibiting the byproduct formation. Consequently, humin formation is markedly restrained and the humins form predominantly from sorbitol, while isomerization is fully suppressed. With this method, the direct dehydration–esterification of sorbitol in various C2–C8 fatty acids can be achieved over recyclable H-beta (Si/Al = 20), giving selectively the corresponding isosorbide esters within a very short reaction time in excellent 79–84% yields including 59–65% diesters. This study opens a straightforward way through MIBK mediation for selective removal and functionalization of hydroxyl groups in biobased polyhydroxylated molecules into valuable oxygenates.