Multiple sclerosis (MS) is a chronic neurological disorder marked by demyelination and inflammation within the central nervous system. Patients frequently experience present with a range of symptoms, including visual disturbances, ataxia, tremors, motor weakness, fatigue, depression, spasticity, pain, bladder-bowel dysfunction, and cognitive impairment. Among these, fatigue is one of the most commonly reported and disabiling symptoms, affecting approximately 80% of patients and significantly diminishing their quality of life. The pathophysiology of MS realted-fatigue is complex and cannot be explained by a single mechanism. Current evidence indicates the involvement of multiple pathways, including neuroimmune dysfunction (characterized by elevated pro-inflammatory cytokines and decreased anti-inflammatory cytokines), monoaminergic deficits (such as reduced serotonin and dopamine availability in key brain regions), neuroendocrine system abnormalities (notably hyperactivation of the hypothalamic-pituitary-adrenal axis), and structural brain changes (including brain atrophy and increased lesion burden). In addition, secondary factors like depression and sleep disorders may intensify the severity of fatigue. Nevertheless, research into the primary mechanisms underlying fatigue remains limited, with most studies involving small sample sizes. In summary, fatigue in MS is a multifactorial symptom that significantly affects patients’ daily lives. Clinical practice should incorporate routine fatigue assessment, and further comprehensive research is necessary to elucidate its underlying mechanisms. Optimizing treatment strategies, including both pharmacological and nonpharmacological interventions, is essential, with personalized approaches playing a pivotal role in effective management.