A comprehensive reaction-path search for the oligomerization of 5-(hydroxymethyl)furfural (HMF) based on quantum chemical calculations was conducted to clarify the mechanism of humin formation in the oxidation of HMF to furan-2,5-dicarboxylic acid (FDCA), in which humin is a typical macromolecular byproduct. The present procedure repeatedly utilizes the multi-component artificial-force-induced reaction (MC-AFIR) method to investigate multistep oligomerization reactions. Although humin formation has been reported even in reagent-grade HMFs with 97–99% purity during their storage at low temperatures, no direct addition path of two HMFs with <185 kJ mol−1barrier has been found, suggesting humin formation is caused by a reaction with impurities. Based on the reaction conditions, we considered the reactions of HMF + H2O, HMF + OH−, and HMF + O2and identified three reaction paths with <65 kJ mol−1barrier for the reaction of HMF + OH−. Further, the suppression of humin formation by the acetal protection of HMF is computationally confirmed.