The exceptional biocompatibility of Zn‐based single‐atom nanozymes (SAzymes) has led to extensive research in their application for disease diagnosis and treatment. However, the fully occupied 3d10 electron configuration has seriously hampered the enzymatic‐like activity of Zn‐based SAzymes. Herein, a B‐doped Zn‐based SAzymes is fabricated by carbonizing zeolite‐like Zn‐based boron imidazolate framework at different temperatures (Zn‐SAs@BNCx, x = 800, 900, 1000, and 1100 °C). The formed B─N bond yielded a local electric field, which changes the position of the d‐band center and improved the oxidation state of Zn by facilitating the electron transfer from Zn to N to B. These changes enhanced the adsorption and activation of H2O2 and O2 by Zn‐SAs@BNC1000, increasing the nanozymes’ multi‐enzyme catalytic activity. B doping led to 24.81‐, 32.37‐, and 13.98‐fold increase in the peroxidase‐, oxidase‐ and catalase‐like, respectively, catalytic efficiency (Kcat/Km) of Zn‐SAs@BNC1000 when compared with no B doping. In addition, Zn‐SAs@BNC1000 showed excellent ability to kill tumor cells both in vitro and in vivo. This study demonstrates that the modulation of the electron configuration of Zn is an effective strategy to develop efficient anti‐tumor approaches by boosting the enzymatic activity of Zn‐based SAzymes.