Exercise as a non-pharmacological measure is important to increase the brain plasticity hence improving cognitive performance as well as mental health. This narrative review describes in depth the hierarchical multiscale processes of neuroplasticity to exercise, including the presence of neurotrophic factor regulation, cellular metabolic adaptations and neurotransmitter remodeling, up to the structure and functional reorganization of brain networks as seen through neuroimaging, and concluding with adaptive cognitive and behavioral outcomes. We further investigate the role of personal variations in genetic time and social environments in moderating the neuroplasticity of exercise. Furthermore, the review identifies the importance of combining multimodal visualization methods with computational models in generating accurate workout prescriptions and their potential of translation into clinical and educational practice. Lastly, the research problems and “grand challenges” are addressed, with a focus on the importance of exercise as a pleiotropic behavior-intervention and its general implications to the area of promoting brain health.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are prevalent neurodevelopmental disorders in childhood and adolescence in which neuroimmune dysregulation and altered microglial function have been increasingly implicated, albeit with substantially different levels of human versus preclinical evidence. Preclinical (in vitro and rodent) studies indicate that contracting skeletal muscle secretes bioactive exercise-induced factors (exerkines)—including irisin, cathepsin B, lactate, and extracellular vesicles—that can directly cross or indirectly signal across the blood–brain barrier, modulate microglial inflammatory states, and support synaptic plasticity. However, whether this complete peripheral-to-central cascade operates to normalize synaptic pruning in children and adolescents with ASD or ADHD remains unconfirmed. In this review, we propose the developmental muscle–microglia axis as a hypothesis-generating conceptual framework and specifically focus on its intersection with pubertal maturation. We critically synthesize in vitro, animal, and human evidence on how key exerkines and multi-pathway brain-derived neurotrophic factor (BDNF) regulation may interact with surging sex hormones during the pubertal transition to influence microglial activity and neuroepigenetic states. Furthermore, we frame modality-specific exercise parameters (FITT-VP model) and multimodal wearable/biomarker closed-loop monitoring as candidate hypotheses and conceptual proposals for future clinical trials in youth with ASD and ADHD, while highlighting methodological limitations, safety considerations, and translational gaps.