The incidence of neurodegenerative diseases has been steadily increasing. Exercise has been shown to facilitate communication between skeletal muscle and brain. However, the specific signaling molecules secreted by skeletal muscle during exercise and their roles in muscle-brain crosstalk, particularly in the regulation of neuroplasticity, cognitive function, and neuroprotection, remain unclear. This review explores the roles of exercise-induced, skeletal muscle-derived signaling molecules in muscle-brain crosstalk, with a focus on the mechanisms by which myokines (e.g., BDNF, irisin), metabolic products (e.g., lactate), and other relevant signaling molecules influence neuroplasticity, cognitive function, and neuroprotection. These mechanisms include promoting neuronal survival, synaptic plasticity, and neurogenesis, as well as interacting with neurotransmitters in the brain to exert anti-inflammatory, neuroprotective, and metabolic regulatory effects. Furthermore, myokines play an active role in the prevention and treatment of metabolic diseases such as diabetes and obesity. This article aims to provide scientific evidence for the application of exercise interventions in maintaining brain health and in the prevention and treatment of neurodegenerative diseases.