Mitochondria are crucial sites for biological oxidation and substance metabolism and plays a vital role in maintaining intracellular homeostasis. When mitochondria undergo oxidative damage or dysfunction, they can harm the organism, leading to various reactive oxygen species (ROS)-related diseases. Therefore, therapies targeting mitochondria are a strategy for treating multiple diseases. Many nanozymes can mimic antioxidant enzymes, which enables them to eliminate ROS to mitigate mitochondrial dysfunction. The therapeutic approaches and drugs targeting the mitochondrial electron transport chain (ETC) have emerged as effective treatments for oxidative stress-related diseases resulting from mitochondrial respiratory chain disorders. Therefore, nanozymes that can regulate homeostasis in the mitochondrial ETC have emerged as effective therapeutic agents for treating oxidative stress-related diseases. In addition, benefit from the controllability and modifiability of nanozymes, their modification with TPP, SS-31 peptide, and mitochondrial permeability membrane peptide to eliminate ROS and repair mitochondrial function. The nanozymes that specifically target mitochondria are powerful tools for the treatment of ROS-associated disorders. We discussed the design strategies pertaining to mitochondrion-targeted nanozymes to treat various diseases to develop more efficacious nanozyme tools for the treatment of ROS-related diseases in the future.