A highly efficient and facile thermal multicomponent cascade reaction of readily available 4-oxo-4H-chromene-3-carbaldehydes with cyanoacetates or cyanoamides and anilines or aliphatic amines under solvent and catalyst-free conditions was developed for the synthesis of a range of polysubstituted 2-aminopyridine derivatives in good to excellent yield. This protocol proceeds via a cascade reaction of Knoevenagel condensation, nucleophilic addition, intramolecular Michael addition, and ring opening. As an application of this methodology, the antibacterial activities of some of the synthetic compounds were evaluated.