Background: Multiple sclerosis (MS) is a neuroinflammatory condition with a prevalence of about 309.2 per 100,000 people in the United States. We aim to identify MS-related mortality trends in the USA from 1999 to 2020, stratified by age, sex, race, and geography, and its correlation with sunlight. Methods: Death certificates from the CDC-WONDER database were examined for adults aged >= 25 years. Crude rates (CR) and age-adjusted mortality rates (AAMRs) per 1,000,000 persons and annual percent change (APC) were calculated. We also retrieved data for daily sunlight from 1999 to 2011. Results: From 1999 to 2020, a total of 121,694 deaths occurred due to MS. The AAMR rose from 23.6 in 1999 to 29.7 in 2020 (APC 0.65), with a stable trend till 2018 (APC-0.22) followed by an abrupt increase towards 2020 (APC 9.27). Women had higher AAMR than men. Non-Hispanic (NH) Whites exhibited the highest AAMR (28.5), followed by NH Blacks (25.9), NH American Indians/Alaska Natives (9.6), Hispanics or Latino (6.8), and NH Asian or Pacific Islanders (1.9). AAMRs also varied substantially by region (Midwest: 32.4; Northeast: 26.9; West: 26.2; South: 19.4). States with the highest AAMRs were Montana, Wyoming, Colorado, and Oregon. The states with lower daily sunlight had higher AAMRs (r r =-0.559, p = 0.000). AAMRs were comparable in urban (25) and rural (26.3) areas. Most deaths occurred in medical facilities (33.92 %) and nursing homes / long-term care (30.80 %), followed by home (27.79 %), and hospice (4.06 %). Adults >= 65 years depicted the highest mortality rates (CR 64.4) while adults aged 25 to 44 years showed the lowest rates (CR 4.6). Conclusion: We found an overall stable trend in MS-related mortality rates in the US till 2018 with a sharp increase thereafter. We observed highest mortality among women and NH White adults, among residents of Midwest and Northeast regions, and among adults >= 65 years. Higher disease burden in recent years calls for devising timely policies focused on these high-risk populations.