The impact of exercise on mental health, on cognition, brain function and brain structure as well as the possible underlying molecular systems important for maintaining neural function and plasticity has been extensively examined. Moreover, numerous studies have reinforced t the important and beneficial role of exercise for those with neurological disorders. This article reviews general aspects of physical exercise against neurodegenerative diseases and the relevant contributions of physical exercise programs as complementary therapy for epilepsy. We first give an overview of the plasticity induced by exercise in the damaged brain, the impact of exercise in reducing brain injury as well as in delaying onset of and decline in several neurodegenerative diseases. We address the relationship between epilepsy and exercise and report the neuroprotective and antiepileptogenic effects of exercise on epilepsy based on experimental and clinical studies. Overall, we conclude that physical or sport activities represent an exciting intervention that should be integrated with conventional therapy for the improvement of brain function and resistance to neurodegenerative diseases as well as a complementary non-pharmacological treatment of epilepsy.