The development of novel methods to obtain biofuels and chemicals from biomass has been an immediate issue in both academic and industrial communities. The present work introduces a new route to synthesize 5-hydroxymethyl furfural (5-HMF) in a one-vessel system through a tandem pathway involving decrystallization, depolymerization and conversion of microcrystalline cellulose (MCC) in a molten hydrate solution. A 71.62 wt% ZnCl₂ aqueous solution was employed as the reaction media and methylisobutylketone (MIBK) as the extracting solvent in the reaction system. A yield of 80.6 mol% of 5-HMF was obtained at 150 °C with a HCl concentration of 0.2 mol L⁻¹ in the solution for 40 min. The aqueous phase can be reused without significant loss of catalytic activity.