A sedentary lifestyle is now known as a critical risk factor for accelerated aging-related neurodegenerative disorders. In contract, having regular physical exercise has opposite effects. Clinical findings have suggested that physical exercise can promote brain plasticity, particularly the hippocampus and the prefrontal cortex, that are important for learning and memory and mood regulations. However, the underlying mechanisms are still unclear. Animal studies reveal that the effects of physical exercise on promoting neuroplasticity could be mediated by different exerkines derived from the peripheral system and the brain itself. This book chapter summarizes the recent evidence from clinical and pre-clinical studies showing the emerging mediators for exercise-promoted brain health, including myokines secreted from skeletal muscles, adipokines from adipose tissues, and other factors secreted from the bone and liver.