INTRODUCTION: Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory demyelination in the central nervous system. Functional Magnetic Resonance Imaging (fMRI) has emerged as an effective method for studying MS pathology. This review provides a comprehensive overview of fMRI applications, clarifying alterations in brain activity and identifying relevant biomarkers. METHODS: A systematic search of electronic databases and manual reference list checks at March 2024 yielded 470 articles. After duplicate removal, 456 articles underwent screening, 44 were assessed in full, and 12 systematic reviews and meta-analyses met inclusion criteria. Quality assessment was conducted. RESULTS: Included studies reported high methodological quality. fMRI revealed decreased functional connectivity within the default mode network, correlating with impaired information processing speed, and increased connectivity in compensatory networks during working memory tasks. Graph theory metrics identified disrupted global efficiency and clustering in functional networks, linked to gray matter atrophy. Neuroplasticity studies demonstrated cortical reorganization after cognitive rehabilitation, particularly in the prefrontal cortex. MS-related fatigue was associated with altered anterior cingulate cortex and thalamic activity, while depression correlated with reduced amygdala-prefrontal connectivity. DISCUSSION: fMRI has enhanced understanding of MS, revealing specific neural correlates of cognitive decline, neuroplasticity, fatigue, and depression. However, variability in MS subtypes and non-standardized protocols hinder consistency, while motion artifacts and cerebral blood flow changes complicate interpretation. Standardizing imaging protocols and integrating novel techniques could improve reliability and enable clinical applications to optimize patient monitoring and interventions.