Alzheimer disease (AD) is the most common type of dementia in individuals over 65 years of age. The neuropathological hallmarks of the condition are Tau neurofibrillary tangles and Amyloid-β senile plaques. Moreover, certain susceptible regions of the brain experience a generalized lack of neural plasticity and marked synaptic alterations during the progression of this as yet incurable disease. One of these regions, the hippocampus, is characterized by the continuous addition of new neurons throughout life. This phenomenon, named adult hippocampal neurogenesis (AHN), provides a potentially endless source of new synaptic elements that increase the complexity and plasticity of the hippocampal circuitry. Numerous lines of evidence show that physical activity and environmental enrichment (EE) are among the most potent positive regulators of AHN. Given that neural plasticity is markedly decreased in many neurodegenerative diseases, the therapeutic potential of making certain lifestyle changes, such as increasing physical activity, is being recognised in several non-pharmacologic strategies seeking to slow down or prevent the progression of these diseases. This review article summarizes current evidence supporting the putative therapeutic potential of EE and physical exercise to increase AHN and hippocampal plasticity both under physiological and pathological circumstances, with a special emphasis on neurodegenerative diseases and AD.