HDAC3 is a specific and crucial member of the HDAC family. It is required for embryonic growth, development, and physiological function. The regulation of oxidative stress is an important factor in intracellular homeostasis and signal transduction. Currently, HDAC3 has been found to regulate several oxidative stress-related processes and molecules dependent on its deacetylase and non-enzymatic activities. In this review, we comprehensively summarize the knowledge of the relationship of HDAC3 with mitochondria function and metabolism, ROS-produced enzymes, antioxidant enzymes, and oxidative stress-associated transcription factors. We also discuss the role of HDAC3 and its inhibitors in some chronic cardiovascular, kidney, and neurodegenerative diseases. Due to the simultaneous existence of enzyme activity and non-enzyme activity, HDAC3 and the development of its selective inhibitors still need further exploration in the future.