In the present study, we fabricated hollow cubic CuxO nanoparticles (∼23 nm) incorporated with CNF (HC-CuxO/CNF) through controlled thermal oxidation of solid cubic Cu2O nanoparticles (∼21 nm) supported on carbon nanofibers (SC-Cu2O/CNF) under airflow, exploiting the nanoscale Kirkendall effect. These hollow CuxO nanocubes with increased surface areas exhibited outstanding catalytic activity for unsymmetrical chalcogenide synthesis under ligand-free conditions.