BACKGROUND: The epidemiology of multiple sclerosis (MS) is complex due to the interaction of various risk factors. This study assesses the global, regional, national and sub-national burden of MS and predicts future trends. METHODS: Data from the Global Burden of Disease Study 2021 was analyzed to assess the epidemiology of MS from 1990 to 2021. Data from the World Bank was used to determine the socio-demographic predictors of MS prevalence using multivariate analysis. RESULTS: Globally, 1.89 million people live with MS, with over 62,000 new cases diagnosed in 2021. The global prevalence of MS is 23.9 cases per 100,000 population, with a continuous increase over the past three decades. North America and Western Europe had the highest prevalence, incidence, disability-adjusted life-years (DALYs), and mortality rates. Countries with the highest prevalence were Sweden (219 /100,000 population), Canada (182), Norway (176), Ireland (163), and the UK (158). Analysis of subnational level data from US revealed that northern states such as Utah, Montana, and Rhode Island had incidence rates double those of southern states such as Hawaii, Mississippi and Louisiana. CONCLUSIONS: The burden of MS is rising worldwide, especially in developed countries. To reduce this burden, it is essential to understand the distribution and risk factors of MS, and to address healthcare disparities in early diagnosis, access to treatment and social services.