As the next generation of artificial enzymes, nanozymes have shown unique properties compared to its natural counterparts, such as stability in harsh environment, low cost, and ease of production and modification, paving the way for its biomedical applications. Among them, tumor catalytic therapy mediated by the generation of reactive oxygen species (ROS) has made great progress mainly from the peroxidase-like activity of nanozymes. FeO nanozymes, the earliest type of nanomaterial discovered to possess peroxidase-like activity, has consequently received wide attention for tumor therapy due to its ROS generation ability and tumor cell killing ability. However, inconsistent results of cytotoxicity were observed between different reports, and some even showed the scavenging of ROS in some cases. By collectively studying these inconsistent outcomes, we raise the question whether surface modification of FeO nanozymes, either through affecting peroxidase activity or by affecting the biodistribution and intracellular fate, play an important role in its therapeutic effects. This review will go over the fundamental catalytic mechanisms of FeO nanozymes and recent advances in tumor catalytic therapy, and discuss the importance of surface modification. Employing FeO nanozymes as an example, we hope to provide an outlook on the improvement of nanozyme-based antitumor activity.