Nanozymes are promising alternatives to natural enzymes, but their use remains limited owing to poor specificity. For example, CeO activates HO and displays peroxidase (POD)-like, catalase (CAT)-like, and haloperoxidase (HPO)-like activities. Since they unavoidably compete for HO, affecting its utilization in the target application, the precise manipulation of reaction specificity is thus imperative. Herein, we showed that one can simply achieve this by manipulating the HO activation pathway on pristine CeO in well-defined shapes. This is because the coordination and electronic structures of Ce sites vary with CeO surfaces, wherein the (100) and (111) surfaces display nearly 100% specificity toward POD-/CAT-like and HPO-like activities, respectively. The antibacterial results suggest that the latter surface can well-utilize HO to kill bacteria (cf., the former), which is promising for anti-biofouling applications. This work provides atomic insights into the synthesis of nanozymes with improved activity, reaction specificity, and HO utilization.