Vitamin E is one of the most widely used antioxidants, extensively applied in the medical and food industries. However, its susceptibility to oxidation poses significant challenges during production, storage, and transportation. In recent years, a derivative of Vitamin E—Vitamin E succinate (VES) has garnered increasing attention. VES not only retains the biological functions of Vitamin E but also exhibits excellent stability and unique anti-tumor properties. The main methods for preparing VES include chemical synthesis and enzymatic synthesis. Enzymatic synthesis has become a popular research topic due to its environmental friendliness and high efficiency. Nevertheless, the high cost and poor reusability of free enzymes severely limit the industrial application of this method. Designing enzyme-friendly solvents and immobilized enzyme technologies has proven to be effective strategies to overcome these limitations. In this study, the synthesis of VES was employed as a model reaction to integrate immobilization and solvent design strategies. The lipase was immobilized in a dual-functional macroporous resin, combined with a novel deep eutectic solvent, significantly enhancing the performance of lipase. Under the optimal conditions, the experimental results revealed a VES yield of 99.3%. When scaled up tenfold, the system achieved a 99.1% esterification yield, with the catalytic activity remaining above 80.0% even after five reuse cycles. Notably, molecular dynamics simulation results indicated that the deep eutectic solvent has excellent biocompatibility, which enhances the stability and reusability of lipase. Furthermore, this solvent improves the affinity of lipase for the substrate, thereby increasing the yield of VES. The synthetic strategy developed in this study is environmentally friendly, catalytically efficient, and offers broad applications in the field of biosynthesis.