Abstract Reactive oxygen species (ROS) generated by piezoelectric materials under mechanical stimulation in piezodynamic therapy (PZDT) show great potential in biomedical applications, including bone regeneration, wound healing, antibacterial treatment, and cancer therapy. These ROS induce cancer cell death via oxidative stress, enhance tissue regeneration through redox‐mediated pathways, and exert strong antibacterial effects by disrupting microbial membranes and biomolecules. However, excessive ROS can cause harmful oxidative stress, chronic inflammation, and damage to healthy tissues, underscoring the need for smart piezoelectric materials that can both generate ROS for treatment and scavenge excess ROS to maintain redox balance. This review examines ROS balancing mechanisms and strategies to regulate pro‐oxidant (therapeutic) and antioxidant (protective) effects for safe and effective therapies. Key factors influencing ROS balancing behavior, detection techniques for optimized ROS control, various design strategies for ROS modulation, and their biomedical applications in PZDT are discussed. Finally, the clinical implications and future directions for piezoelectric ROS balancing are presented, emphasizing the need for further research to optimize the generation‐scavenging balance. It is anticipated that this topical review will be beneficial for designing advanced piezoelectric systems for biomedical use, ensuring precise regulation of the pro‐ and anti‐inflammatory phases of therapy.