Purpose: Hispanic/Latino adults on the Texas-Mexico border have high rates of chronic disease. Neighborhoods can influence health, though there is a limited research on neighborhood environment and health in Hispanics/Latinos. The purpose of this study was to assess the relation of neighborhood environment with health variables in Hispanic/Latino adults, including physical activity [PA], depression, anxiety, and lab-assessed conditions (type 2 diabetes, metabolic syndrome, and chronic inflammation). Methods: Participants were randomly-selected from a Hispanic/Latino cohort on the Texas-Mexico border. Neighborhood environment, self-reported PA, anxiety, and depression were assessed through questionnaires. Laboratory values determined Type 2 diabetes, metabolic syndrome, and C-reactive protein (CRP). We conducted multivariable linear and logistic regression analyses to assess the associations of neighborhood environment and health variables, controlling for covariates. Results: Participants (n = 495) were mostly females, without insurance. After controlling for covariates, crime (Adjusted Odds Ratio [AOR] = 1.59 (95%CI 1.06-2.38), no streetlights (AOR = 1.65, 95%CI 1.06-2.57), and traffic (AOR = 1.74, 95%CI 1.16-2.62) were all significantly associated with anxiety. Only traffic was significantly associated with depression (AOR = 1.61, 95%CI1.05-2.47). A lack of nearby shops (AOR = 0.57, 95%CI 0.38-0.84) and no one out doing PA (AOR = 0.53, 95% CI 0.34-0.83) were both significantly associated with lower odds of meeting PA guidelines. A lack of nearby shops was associated with a 26% increase in the CRP value (β = 0.26, 95%CI 0.04-0.47). Discussion: Several neighborhood environment variables were significantly associated with mental health, PA and CRP, though estimates were small. The neighborhood environment is a meaningful contextual variable to consider for health-related interventions in Hispanic/Latino adults, though more study is needed regarding the magnitude of the estimates. Trial registration: NCT01168765.