Herein, the L-serine-functionalized metal−organic framework nanostructure is obtained via a simple two-step postsynthetic modification strategy. Interesting properties of serine, such as the existence of both acidic and basic groups, provide amphoteric active sites on UiO-66-NH 2 that are not accessible through direct synthesis. In this sense, an excess amount of 1,6 hexamethylene diisocyanate is primarily used as a linker to allow the conversion of nucleophilic groups in UiO-66-NH 2 to isocyanate as a suitable electrophile group. L-serine reacted with isocyanate to generate the corresponding urea derivative. SEM, TEM, and nitrogen adsorption analyses confirm an average particle size of approximately 24 nm and a pore size of 6.68 nm within the framework. Notably, the synthesized amphoteric nanomaterial exhibited high catalytic activity, stability, and durability in the solventfree procedures in synthesizing a diverse range of 4H-pyrano[2,3-b] pyridine-3,6-dicarbonitriles and octahydropyrimido [4,5 b][1,8]naphthyridine-7-carbonitriles. Moreover, the catalyst was easily separated�indicating a substantial decrease of catalytic activity upon five consecutive runs in the reaction.