The renewable 5-hydroxymethylfurfural (5-HMF) has gained a wide interest from the chemistry community as a valuable biobased platform opening the way to further functionalization. Despite an impressive number of publications reporting either its preparation or its functionalization, its direct use in fine chemistry, and especially in multi-component reaction (MCR), is less reported. Here, we report a complete study of the use of 5-HMF in the Hantzsch dihydropyridines synthesis. The strategy was applied to a scope of β-dicarbonyl molecules (including b-ketoesters and 1,3-diketones) in a 3-component procedure leading to a series of symmetrical 1,4-dihydropyridines derived from 5-HMF in excellent yields. The study was extended to the 4-component protocol using one equivalent of a β-ketoester and one equivalent of 5,5-dimethyl-1,3-cyclohexanedione (dimedone), which efficiently provided the corresponding unsymmetrical dihydropyridines.