Background: The association between acculturation and physical activity (PA) among Mexican American (MA) adults is not understood. This study assessed potential mediating factors that may explain these associations among 75 healthy MA adults [age: 37.5 (9.3) y; 65.3% female]. Methods: Secondary data analysis using hierarchical logistic regression examined whether perceived environmental barriers, social support, and intention to exercise potentially mediated relationships between acculturation level, and total and leisure-time moderate to vigorous PA (MVPA). Data were collected via questionnaire. Results: Most participants (67%) reported lower average household monthly incomes ($0–$3000), completed some college or obtained a college degree (64.4%), and were first generation immigrants (59%). Acculturation was associated with greater odds of engaging in total MVPA [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.2–2.4] and leisure-time MVPA (OR = 1.6; 95% CI, 1.1–1.2). Perceived environmental barriers were associated with greater odds of engaging in both total and leisure-time MVPA (OR = 4.3; 95% CI, 2.1–5.8 and OR = 5.5; 95% CI, 2.0–7.0, respectively), and social support was associated with greater odds for total MVPA (OR = 3.7; 95% CI, 1.1–6.4). Conclusions: Results provide preliminary evidence for mediating factors that may explain the relationship between acculturation level and PA among MA adults. Contradicting prior evidence, results suggest that PA engagement, despite perceived environmental barriers, is possible among MA adults having stronger social support.