An efficient and straightforward four-component synthetic protocol has been developed to synthesize imidazo[1,2-a]pyridines and imidazo[1,2,3-ij][1,8]naphthyridine derivatives incorporating medicinally privileged heterosystems from heterocyclic ketene aminals, aldehydes, diketene, and amines via cascade reactions, including diketene ring-opening, Knoevenagel condensation, aza-ene reaction, imine-enamine tautomerization, cyclocondensation, and intramolecular S(N)Ar. This strategy can provide an alternative approach for easy access to the highly substituted imidazo[1,2-a]pyridine derivatives in moderate to good yields using four simple and readily available building blocks under mild conditions. Importantly, the unusual splitting peaks in the (1)H NMR spectra of the products derived from heterocyclic ketene aminals with an o-halogen atom on the aryl ring were explained reasonably by varying the temperature in NMR analysis.