The present study assessed how the adaptation to American culture by United States (U.S.)-born and foreign-born Hispanics living in the U.S. may influence stress-related physiological aspects that may impair health. Data on 8,360 Hispanics living in the U.S. categorized as U.S.-born (n = 3347) and foreign-born (n = 5013) from NHANES 1999–2010 (ages 18–85) were used. Stress-related physiological impact was measured by the allostatic load index (ALoad). Adaptation to American culture was evaluated through three acculturation-related measures. The average age was 39.39 years in a sample where 51% were males. ALoad was classified as no load (15.41%), low load (55.33%), and high load (29.24%). The U.S.-born Hispanics showed higher ALoad compared to foreign-born Hispanics (p < 0.001). Among foreign-born Hispanics, length of residence (LOR) and age of arrival in the U.S. (AOA) were associated with higher ALoad scores (p < 0.05), and in U.S.-born Hispanics, age and sex were positively associated and education was negatively associated with ALoad scores (p < 0.05). Adaptation to American culture in foreign-born Hispanics living in the U.S. appears to influence levels of ALoad in this population.