Herein, a hitherto unreported approach for the synthesis of pyrazole/isoxazole-fused naphthyridine derivatives by a three-component domino reaction of arylglyoxal monohydrate, 5-amino pyrazole/isoxazole, and indoles in acetic acid medium has been reported. In this method, four bonds (2 C-C and 2 C-N) form in one-pot with the concomitant formation of two new pyridine rings via indole ring opening and double cyclization reactions. This methodology is also applicable in gram-scale synthesis. The reaction mechanism was studied by isolating and characterizing the reaction intermediates. Along with complete characterization of all the products, the structure of the product 4o was unambiguously confirmed by single crystal X-ray diffraction.