A concise and efficient one-pot synthesis of functionalized [1,8]naphthyridine derivatives via a three-component domino reaction of glutaraldehyde, malononitrile, and β-ketoamides, under catalyst-free conditions in an environmentally friendly medium (ethanol) is described. The main advantages of this protocol are short reaction times, practical simplicity, high yields, catalyst-free conditions, cheap and benign solvents, and high regio- and stereo-selectivities.