Introduction: Recent research has highlighted an increased incidence of ischemic stroke (IS) in young adults, along with a higher percentage of vascular risk factors at younger ages. This study aimed to estimate the in-hospital incidence of IS and associated comorbidities by sex and age group in Spain. Methods: A retrospective analysis of the Spain Nationwide Inpatient Sample database from 2016 to 2019 was conducted, which included adult patients with IS. In-hospital incidence and mortality rates were estimated, and a descriptive analysis of the main comorbidities was performed, stratified by sex and age groups. Results: A total of 186,487 patients were included, with a median age of 77 (IQR 66–85) years and 53.3% were male. Of these, 9162 (5%) were aged between 18 and 50 years. The estimated incidence of IS in adults younger than 50 years ranged from 11.9 to 13.5 per 100,000 inhabitants during the study period, with a higher incidence in men. The overall in-hospital mortality was 12.6%. Young adults with IS had a higher prevalence of most vascular risk factors compared to the general Spanish population, with a specific distribution according to sex and age. Conclusions: This study provides estimates of the incidence of IS and the prevalence of vascular risk factors and comorbidities associated with IS in Spain, stratified by sex and age, using a national registry of hospital admissions. These findings should be considered in terms of both primary and secondary prevention strategies.