Vacancy control can significantly enhance the performance of photocatalytic semiconductors for water purification. However, little is known about the mechanisms and approaches that could generate stable large vacancies. Here, we report a new mechanism to induce vacancy formation on nanocrystals for enhanced photocatalytic activity: the introduction of mesopores. We synthesized two nanosheet-assembled hierarchical 3D BiOCl mesoporous nanostructures with similar morphology and exposed facets but different nanosheet thickness. Positron annihilation analysis detected unprecedentedly large VBi‴ VO•• VBi‴ VO•• VBi‴ vacancy associates (as well as VBi‴ VO•• VBi‴) on BiOCl assembled from 3-6 nm nanosheets but only VBi‴ VO•• VBi‴ vacancy associates on BiOCl assembled from thicker (10-20 nm) nanosheets. Comparison of vacancy properties with 2D ultrathin 2.7 nm nanosheets (with VBi‴ VO•• VBi‴ and VBi‴) indicates that nanosheet thinness alone cannot explain the formation of such large atom vacancies. On the basis of density functional theory computations of formation energy of isolated Bi vacancy, we show that mesopores facilitate the formation of large vacancies to counterbalance thermodynamic instability caused by incompletely coordinated Bi and O atoms along the mesopore perimeters. We corroborate that the extraordinarily large VBi‴ VO•• VBi‴ VO•• VBi‴ vacancy associates facilitate photoexcitation of electrons and prevent the recombination of electron-hole pairs, which significantly enhances photocatalytic activity. This is demonstrated by the rapid mineralization of bisphenol A (10-5 M) with low photocatalyst loading (1 g L-1), as well as enhanced bacterial disinfection. Improved electron-hole separation is also corroborated by enhanced photocatalytic reduction of nitrate.