Abstract5-Methylfurfural (MF) is a very useful chemical. Selective hydrogenation of biomass platform molecule 5-(hydroxymethyl)furfural (HMF) to MF using H₂ as the reducing agent is very attractive, but challenging because hydrogenation of C=O bond in HMF is more favourable than C–OH both kinetically and thermodynamically, and this route has not been realized. In this work, we prepare isolated single atomic catalysts (SACs) Pt₁/Nb₂O₅-Ov, Pd₁/Nb₂O₅-Ov, and Au₁/Nb₂O₅-Ov, in which single metal atoms are supported on oxygen defective Nb₂O₅ (Nb₂O₅-Ov). It is discovered that the SACs can efficiently catalyze the hydrogenation of HMF to MF using H₂ as the reducing agent with MF selectivity of >99% at complete conversion, while the selectivities of the metal nanocatalysts supported on Nb₂O₅ are very poor. A combination of experimental and density function theory (DFT) studies show that the unique features of the SACs for the reaction result from the cooperation of the Nb and Pt sites near the interface in the Pt₁/Nb₂O₅-Ov. The Pt atoms are responsible for the activation of H₂ and the Nb sites activate C-OH in the reaction. This work opens the way for producing MF by direct hydrogenation of biomass-derived HMF using H₂ as the reductant.