A carbonyl reductase variant, SmCRM5, from Serratia marcescens was obtained through structure-guided directed evolution. The variant showed improved specific activity (U mg-1) towards most of the 16 tested substrates and gave high stereoselectivities of up to 99% in the asymmetric synthesis of 13 γ-/δ-lactones. In particular, SmCRM5 showed a 13.8-fold higher specific activity towards the model substrate, i.e., 5-oxodecanoic acid, and gave (R)-δ-decalactone in 99% ee with a space-time yield (STY) of 301 g L-1 d-1. The preparative synthesis of six δ-lactones in high yields and with high enantiopurities showed the feasibility of the biocatalytic synthesis of these high-value-added chemicals, providing a cost-effective and green alternative to noble-metal catalysis.