Importance Nervous system health is a major contributor to population health, which is directly affected by neurological conditions and other disorders where nervous system damage occurs. Objective To quantify aggregated health loss from diseases affecting the nervous system, including neurological disorders; neurodevelopmental disorders; congenital, neonatal, and systemic illnesses; and infectious diseases in the United States. Design, Setting, and Participants This is a cross-sectional study of the Global Burden of Disease 2021 study data for nervous system health loss confined to the United States from 1990 through 2021 among the entire US population. Data analysis was performed from December 2021 to January 2025. Exposure Thirty-six unique conditions that cause harm to the nervous system. Main Outcomes and Measures Totals and age-standardized estimates with 95% uncertainty intervals (UIs) for disability-adjusted life-years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), total attributable deaths (where applicable), and prevalence. Results In 2021, of the US population of 332.7 million, disorders affecting nervous system health impacted 180.3 million (95% UI, 170.7 million to 190.4 million) US individuals and were the top cause of disability, with 16.6 million (95% UI, 12.9 million to 20.9 million) DALYs. The most prevalent conditions were tension-type headache (121.9 million; 95% UI, 109.4 million to 135.1 million), migraine (57.7 million; 95% UI, 50.1 million to 66.1 million), and diabetic neuropathy (17.1 million; 95% UI, 14.4 million to 19.9 million). Conditions with the greatest collective disability were stroke (3.9 million DALYs; 95% UI, 3.5 million to 4.2 million DALYs), Alzheimer disease and other dementias (3.3 million DALYs; 95% UI, 1.6 million to 6.9 million DALYs), diabetic neuropathy (2.2 million DALYs; 95% UI, 1.5 million to 3.0 million DALYs), and migraine (2.1 million DALYs; 95% UI, 0.4 million to 4.6 million DALYs). Compared with age-standardized metrics in 1990, the prevalence of disorders affecting the nervous system was nearly identical (−0.2%; 95% UI, −1.5% to 1.9%), with decreased attributable deaths (−14.6%; 95% UI, −18.3% to −11.3%) but increased YLDs (9.8%; 95% UI, 4.6% to 16.6%). By state, Mississippi, Alabama, and Louisiana had the largest age-standardized DALY rates, while New York, Massachusetts, and New Jersey had the smallest. Conclusions and Relevance Disorders affecting the nervous system are highly prevalent and cause disability for millions of US individuals, with reduced mortality leading to more YLDS. The United States should prioritize efforts to combat these conditions with development and implementation of new and effective prevention strategies, therapeutics, and focused rehabilitation.