Abstract: Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid (PUFA) for human body, which is highly rich in deep sea fish oil and marine microalgae. Mitochondria are the energy factory of cells. Mitochondrial functions and biogenesis can be regulated by DHA which exhibits antioxidation, anti-inflammatory and anti-cancer activities. This article reviews the research progress of mitochondrial-mediated DHA antioxidation and the possible underlying mechanism. The effects of DHA in eliminating reactive oxygen species (ROS) and regulating mitochondrial biogenesis and functions, as well as the microRNA-mediated DHA antioxidant epigenetic mechanism are addressed, which may provide evidence for better DHA product exploration and application.