Background- The traditional understanding of multiple sclerosis (MS) has focused on scattered focal white matter lesions within the central nervous system. However, recent research has brought attention to MS-associated cortical gray matter lesions. This systematic review aims to comprehensively examine the pathological and clinical aspects of subpial demyelination in the cerebral cortex of MS patients, addressing and resolving the existing controversies in the literature. Methods- Following the guidelines in the Preferred Reporting for Systematic Review and Meta-Analysis (PRISMA), a systematic search was conducted across three databases (PubMed, Scopus, and Web of Science) to review relevant articles. Results and Conclusion- The present paper's findings highlight that subpial cortical demyelination is more prevalent in secondary progressive MS (SPMS). It is postulated that gray matter lesions in MS patients may stem from heightened meningeal inflammation, leading to the formation of specific immune structures and dysregulated molecular immune pathways within the nervous system. Epstein-Barr virus (EBV)-infected cells, particularly those in active lesions, are implicated in triggering a cytotoxic event originating in the meninges and affecting the underlying subpial region. While the cortical region is generally believed to possess significant potential for remyelination, subpial cortical demyelination has been observed to alter the oligodendroglial population in the cerebral cortex, posing obstacles to remyelination. In conclusion, a collaboration of immune structures and mediators may result in subpial cortical demyelination in MS patients, resulting in a progressive disease course and a reduced remyelination activity in the nervous system.