Exercise has been shown to benefit brain structure and function, particularly in aging populations. However, the mechanisms by which exercise exerts its effects, especially in humans, are not fully understood. This review argues that one reason for this knowledge gap is that exercise likely operates through multiple levels of mechanisms. Furthermore, the mechanisms of exercise may vary depending on factors such as age and health state. We discuss the state of evidence at each of three levels of analysis (molecular/cellular, brain structure/function, and mental states and higher-order behaviors) and highlight consistencies across these levels, inconsistencies within them, and knowledge gaps. Lastly, based on these, we speculate about which mechanisms of exercise may be universal across age groups and populations versus those that might be distinct to specific age ranges or populations. There is evidence that aerobic exercise can affect the brain and cognition through different levels of mechanisms at various points in the lifespan. The strongest evidence comes from children and older adults.Exercise has significant promise for mitigating some of the cognitive and brain deficits resulting from a variety of neurologic, non-neurological, and psychiatric conditions.There is a dire need for more rigorous randomized controlled trials (RCTs) of exercise in lesser studied age groups, especially children aged <5 years, adolescents, and young adults.A common limitation of the existing exercise literature relates to the heterogeneous nature of studies (e.g., in terms of design, duration, and included outcomes assessments).