(S)-2-Chloro-1-(3,4-difluorophenyl)-ethanol [(S)-CFPL] is a key chiral intermediate in the manufacture of Ticagrelor. In this study, deep eutectic solvent (DES) was used as the co-solvent, and several reaction parameters were investigated and characterized. It was observed that supplementary of DES could promote the asymmetric reduction of 2‑chloro-1-(3,4-difluorophenyl) ethanone (CFPO) to (S)-CFPL through the biological reduction by recombinant E. coli containing a NADH-dependent reductase CmCR. The high pKa value of carboxylic acid in DES and low viscosity of DES were beneficial to increase cell membrane permeability and enhancement of biocatalytic efficiency. By supplementary of DES ChCl:LA (7.5 vol%) into the bioreaction system, the efficient bioreduction reaction of 100 mM CFPO was achieved via the biocatalysis with whole-cell at 30 °C and pH 7.0, affording (S)-CFPL in 95.9 % yield and optical purity > 99 %. The process was environmentally friendly with high biocatalytic productivity and had potential practicability in the mass production of (S)-CFPL.