Homelessness is a major social determinant of health. We studied the clinical and economic profile of homeless young adults hospitalized with stroke. We studied the National Inpatient Sample database (2002-2017) to evaluate trends of stroke hospitalization, clinical outcomes, and health expenditure in homeless vs non-homeless young adults (<45 years). We identified 3134 homeless individuals out of 648,944 young adults. Homeless patients were more likely to be men, Black adults and had a higher prevalence of cardiometabolic risk factors and psychiatric disorders than non-homeless adults. Both homeless and non-homeless adults had a similar prevalence of ischemic and hemorrhagic stroke. Between 2002 and 2017, hospitalization rates per million increased for both non-homeless (295.8-416.8) and homeless adults (0.5-3.6) (P ≤ 0.01). Between 2003 and 2017, the decline in in-hospital mortality was limited to non-homeless adults (11%-9%), while it has increased in homeless adults (3%-11%) (P < 0.01). The prevalence of acute myocardial infarction (6.8% vs 3.3%, P < 0.01), and acute kidney injury (13.1% vs 9.4%, P < 0.01) was also higher in homeless vs. non-homeless adults. The length of stay and inflation-adjusted care cost were comparable between both study groups. Finally, a higher proportion of homeless patients left the hospital against medical advice than non-homeless adults. Homeless young stroke patients had significant comorbidities, increased hospitalization rates, and adverse clinical outcomes. Therefore, public health interventions should focus on multidisciplinary care to reduce health care disparities among young homeless adults.