Propanediol oxidoreductase from Escherichia coli (FucO) uses NADH/NAD⁺ as cofactors to catalyze the conversion of S-lactaldehyde to S-1,2-propanediol and vice versa. FucO is an attractive enzyme in the search for possible biocatalysts producing alpha-hydroxy aldehydes, which are important for the synthesis of natural products and synthetic drugs. Enzymes catalyzing these types of reactions are unique in catalytic power and stereoselectivity. The usage of FucO in synthetic industry is limited by the restricted substrate scope, which makes FucO inactive with larger phenyl-substituted alcohols. We used re-engineering and directed evolution to enable FucO to catalyze the regio- and enantioselective oxidation of arylsubstituted vicinal diols, such as phenylpropanediols, into alpha-hydroxy aldehyde products. We mutated amino acids considered to restrict the entry into the active site, and modeled the mutants that were most active with the substrates phenylacetaldehyde and S-3-phenyl-1,2-propanediol and performed docking studies with them. As expected, our experimental and in silico results show that the mutations enlarge the active site cavity and enable the mutant enzymes to accommodate the new substrates. We also found specific amino acids in the active site, which need to be conserved to allow the substrates to make stabilizing interactions. Interestingly, an asparagine residue makes the mutant enzymes able to discriminate between phenylacetaldehyde and S-3-phenyl-1,2-propanediol. In conclusion, we successfully re-engineered the specialist enzyme FucO to accept also bulkier molecules as substrates, thereby making it more useful for industrial purposes.