Introduction: Cognitive impairment is a typical sequel and a solid long-term disability predictor that can be screened at early stages post-stroke. However, most routinely used cognitive screening tools were designed to detect dementia, which differs significantly from post-stroke cognitive impairment, including focal cognitive deficits. The Oxford Cognitive Screen (OCS), a cognitive bedside screening tool specifically designed for acute stroke, provides a good alternative for clinical practice. Aim: This study aims at validating an American-Spanish version of the OCS (OCS-Sp) in healthy participants and acute stroke patients. Methods: The original version of the OCS was linguistically and culturally adapted into American Spanish. A total of 152 volunteers were recruited, 87 healthy controls and 65 acute stroke patients. Normative data analysis for determining cut-off scores and psychometric validation and reliability analyses in the stroke cohort were completed. Results: Following a linear regression model demonstrating age, gender, and particularly years of education affecting the performance of the OCS-Sp, the cut-off scores obtained for all subtests were adjusted by these demographic variables. Logistic regression classification analyses revealed that all subtests could discriminate between patients and healthy volunteers. No differences in performance between versions A and B of the test (p > 0.05) were found. The test–retest reliability results in patients showed high agreement between the scores obtained at both time points. Conclusions: The OCS-Sp obtained similar psychometric scores to the original English version, demonstrating its validity and reliability as an instrument to assess cognitive impairments in American Spanish-speaking acute stroke patients.