In the present work, we describe the design and fabrication of a novel, highly efficient, and retrievable silica nanosphere-supported copper catalytic system (SiO2@APTES@DAP-Cu) via immobilization of diacetyl pyridine (DAP) onto amine-functionalized silica nanospheres. The structure of resulting organic-inorganic hybrid SiO2@APTES@DAP-Cu nanocatalyst has been systematically affirmed using various physicochemical characterization techniques such as solid-state C-13 CP-MAS NMR spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, Brunauer-Emmett-Teller surface area analysis, scanning electron microscopy, atomic absorption spectroscopy, energy-dispersive X-ray fluorescence spectroscopy, X-ray diffraction, and elemental analysis. Thereafter, the catalytic performance of the synthesized heterogeneous catalyst has been investigated in oxidative amidation of methyl ketones using hydrogen peroxide as the oxidant and iodine as an additive. It has been found that the nanostructured copper catalyst displays very high efficacy with excellent functional group tolerance and allows the generation of a wide range of amidation products under mild reaction conditions. In addition, the catalyst exhibits remarkable durability as well as good recyclability for several runs with a high consistence in its catalytic activity. Furthermore, this newly developed catalytic protocol is a better alternative to the already-existing methodologies for oxidative coupling of methyl ketones with amines as it is endowed with many outstanding features such as simple work-up procedure, high product yield, cost effectiveness, no use of toxic organic solvents, easy recovery, and reusability of the nanostructured catalyst. It is noteworthy that the use of hydrogen peroxide as a potentially green oxidant is one of the most significant attributes of the present oxidative transformation which renders it economic and environmentally sustainable as water is formed as the sole by-product.