Examine the relationship between physical activity (PA) and allostatic load in Mexican-Americans as well as variations by gender. Self-reported PA as well as cardiovascular, metabolic and inflammatory markers were assessed in 330 Mexican-American adults in the Cameron County Hispanic Cohort (Brownsville, TX, USA). Dependent variables included total allostatic load, blood pressure, metabolic, and inflammatory scores. PA participation was categorized as sedentary, low, moderate, high, and by whether activity was sufficient to meet public health guidelines. Logistic regression analyses were conducted using cross-sectional data, and tested interaction effects of gender and PA. High active participants had lower allostatic load and inflammatory risk than sedentary participants. These relationships held for meeting versus not meeting guidelines. Males meeting guidelines were less likely to have high inflammation than other groups. The data did not suggest a dose-response association. These findings indicate that PA may reduce accumulation of allostatic load, highlighting the importance of a physically active lifestyle across the life span.