Manipulation of the chemical reactivity of two-dimensional materials is a challenge for advancing various nanotechnologies, ranging from electronics to catalysis. In this study, on the basis of first-principles calculations, we demonstrated that the chemical reactivity of h-BN sheets towards O2 can be significantly enhanced via a metal substrate-mediated charge effect. The chemisorption of O2 molecule on the h-BN sheet deposited on Ni, Co, or Cu substrate were almost spontaneous with negligible energy barrier, distinctly different from that on the freestanding h-BN sheet, which has ultra-high chemical stability. In particular, the enhanced oxidation of h-BN sheet can be confined in the nanoscale region due to the localized electronic states in the h-BN sheet. These findings imply a pathway to selectively oxidize h-BN sheet by patterning the metal substrate.