As a potential substitute for petroleum-based terephthalic acid (TPA) in the manufacture of polyesters, 2,5-furandicarboxylic acid has been obtained through several feasible routes. Herein, a new chemo-enzymatic strategy for generating furan-2,5-dicarboxylic acid (FDCA) precursors from sodium gluconate via bio-oxidation and dehydration is presented. By coupling the bio-oxidation of gluconate 5-dehydrogenase with carbonyl reductase PsCR for cofactor regeneration, 5-keto-D-gluconic acid (5KGA), a specific product of D-gluconic acid bio-oxidation and a stable intermediate, was obtained in 99% yield. The statin intermediate ethyl (S)-4-chloro-3-hydroxybutanoate was simultaneously generated as a co-product via cycling cascade catalysis. Subsequently, the yield of the FDCA precursor n-butyl-5-formyl-2-furancarboxylate (nBu-FFCA) generated via5KGA dehydration and esterification reached 77.9%. Key intermediate characterization and theoretical calculations revealed that the decarboxylation and dehydration of cyclic 5KGA to furfural was the main side-reaction that prevented a better yield of dehydrated 5KGA. This route demonstrates good sustainability and market competitiveness compared to the existing FDCA synthesis methods.