Metal-organic frameworks (MOFs) are promising candidates as nanoporous heterogeneous catalysts over other solid catalysts. Herein, utilizing a new tetra-acid ligand and employing high-valent Indium metal source we have strategically developed a 3D robust nanoporous framework, IITKGP-53, which retained its crystallinity over a wide range of pH solutions (2–12). Considering the green synthesis approach IITKGP-53 was explored as a heterogeneous catalyst toward one-pot three-component Strecker reaction under solvent-free condition, with low catalyst loading for a broad range of substrates. Considering practical utility, biologically important natural product, Girgensohnine, was synthesized for the first time by using this catalyst with excellent conversion rate. The substrate binding sites inside the nanopores and host–guest interactions were verified crystallographically by obtaining a substrate inside nanopores of this MOF (aniline@IITKGP-53) and computational modeling. An in-depth theoretical investigation unveiled the most plausible transition states for the first time. This study inaugurates the usage of nanoporous MOFs as heterogeneous catalysts for natural product synthesis.