Candida parapsilosis carbonyl reductases (CpRCR) have been widely used for the reductive conversion of ketone precursors and chiral alcohol products in pharmaceutical industries. The enzymatic enantioselectivity is believed to be related to the shape complementation between the cavities in the enzymes and the substitutions of the ketone substrates. In this work, we reported an unexpected enantioselectivity in the enzyme reductions of dihydrofuran-3(2H)-one (DHF) to (S)-tetrahydrofuran-3-ol (DHF-ol, enantiomeric excess: 96.4%), while dihydrothiophen-3(2H)-one substrate (DHT) was unproductive under the same experimental conditions. To rationalize the exclusive S-configuration and the specific reactivity of DHF, we carried out molecular dynamics simulations for the reacting complexations of DHF with CpRCR, and DHT with CpRCR. Our calculations indicate that DHF preferentially binds to the small cavity near L119, F285, and W286, while the large cavity near the α1 helix was mainly occupied by solvent water molecules. Moreover, the pre-reaction state analysis suggests that the pro-S conformations were more abundant than the pro-R, in particular for DHF. This suggests that the non-polar interaction of substrate C4-C5 methylene contacting the hydrophobic side-chains of L119-F285-W286, and the polar interaction of funanyl oxygen exposing the solvent environment play important roles in the enantioselectivity and reactivity. The phylogenetic tree of CpRCR homologues implies that a variety of amino acid combinations at positions 285 and 286 were available and thereby potentially useful for redesigning enantioselective reductions of 5-membered-ring heterocyclic ketones.