Although a myriad of bioorthogonal prodrugs have been developed, very few of them present both fast reaction kinetics and complete cleavage. Herein, we report a new bioorthogonal prodrug strategy with both fast reaction kinetics (<i>k</i><sub>2</sub>: ∼10<sup>3</sup> M<sup>-1</sup> s<sup>-1</sup>) and complete cleavage (>90% within minutes) using the bioorthogonal reaction pair of <i>N</i>-oxide and boron reagent. Distinctively, an innovative 1,6-elimination-based self-immolative linker is masked by <i>N</i>-oxide, which can be bioorthogonally demasked by a boron reagent for the release of both amino and hydroxy-containing payload in live cells. Such a strategy was applied to prepare a bioorthogonal prodrug for a camptothecin derivative, SN-38, resulting in 10-fold weakened cytotoxicity against A549 cells, 300-fold enhanced water solubility, and "on-demand" activation upon a click reaction both <i>in vitro</i> and <i>in vivo</i>. This novel bioorthogonal prodrug strategy presents significant advances over the existing ones and may find wide applications in drug delivery in the future.