Developing catalysts with optimized surface properties is significant for advanced catalysis. Herein, a rational architectural design is proposed to successfully synthesize yolk-shell nickel molybdate with abundant oxygen vacancies (YS-VO-NMO) via an acid-assisted defect engineering strategy. Notably, YS-VO-NMO with the yolk-shell structure shows complex nanoconfined interior space, which is beneficial to the mass transfer and active sites exposure. Moreover, the defect engineering strategy is of great importance to modulate the surface electronic structure and atomic composition, which contributes to the enrichment of oxygen vacancies. Benefiting from these features, the higher hydrogen peroxide activation is achieved by YS-VO-NMO to produce more hydroxyl radicals compared with untreated nickel molybdate. Consequently, the defect-engineered YS-VO-NMO not only features superior catalytic activity (99.5%) but also retains high desulfurization efficiency after recycling eight times. This manuscript provides new inspiration for designing more promising defective materials via defect engineering and architecture for different applications besides oxidative desulfurization.