In microdroplets, various reactions are known to be accelerated. Yet, controlling chemoselectivity within droplets remains largely unexplored. Here, we show that non-covalent self-assembly in sprayed microdroplets enables selective, catalyst-free, ambient-temperature hydrogenation of multifunctional biomass-derived molecules. Using 5-hydroxymethylfurfural as a model system, we reveal that hydrogen bonding between its hydroxyl and aldehyde groups promotes supramolecular assembly, which selectively shields the carbonyl and hydroxyl moieties while exposing the furan ring to reduction. Spectroscopic measurements and density functional theory calculations confirm that this organization governs site-specific reactivity in the absence of external reductants or metal catalysts and amplify the electric field effect. Substrates lacking analogous hydrogen-bonding motifs undergo competing oxidation, underscoring the mechanistic role of molecular recognition. The strategy extends to furfural and furfuryl alcohol, demonstrating tunable product selectivity. These findings establish a general design principle in which confined microenvironments and supramolecular assemblies cooperate to direct chemoselectivity, offering a sustainable approach to selective transformations beyond conventional catalysis.