RNA-cleaving DNAzymes are useful tools for intracellular metal-ion sensing and gene regulation. Incorporating stimuli-responsive modifications into these DNAzymes enables their activities to be spatiotemporally and chemically controlled for more precise applications. Despite the successful development of many caged DNAzymes for light-induced activation, DNAzymes that can be intracellularly activated by chemical inputs of biological importance, such as reactive oxygen species (ROS), are still scarce. ROS like hydrogen peroxide (H2 O2 ) and hypochlorite (HClO) are critical mediators of oxidative stress-related cell signaling and dysregulation including activation of immune system as well as progression of diseases and aging. Herein, we report ROS-activable DNAzymes by introducing phenylboronate and phosphorothioate modifications to the Zn2+ -dependent 8-17 DNAzyme. These ROS-activable DNAzymes were orthogonally activated by H2 O2 and HClO inside live human and mouse cells.