© 2018, Springer Nature Limited. Objective: To describe the relationship between metabolic health parameters and depressive symptoms and perceived stress, and whether the co-occurrence of these two psychological stressors has an additive influence on metabolic dysregulation in adults at different levels of body mass index (BMI) without diabetes. Methods: Participants without diabetes (N = 20,312) from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study (recruited between 2003–2007) who had a body mass index (BMI) ≥ 18.5 kg/m 2 were included in this cross-sectional analysis. Mean age of sample was 64.4 years, with 36% African American, and 56% women. Depressive symptoms and perceived stress were measured using brief versions of the Center for Epidemiologic Studies Depression (CES-D-4 item) questionnaire and Cohen Perceived Stress Scale (PSS), respectively. Metabolic health parameters included waist circumference, blood pressure (systolic and diastolic), low- and high-density lipoprotein (LDL, HDL) cholesterol, triglycerides, fasting glucose, and high sensitivity C-reactive protein (hs-CRP). Sequentially adjusted general linear regression models (GLM) for each metabolic parameter were used to assess the association between having both elevated depressive symptoms and stress, either of these psychological risk factors, or none with all analyses stratified by BMI category (i.e., normal, overweight, and obesity). Results: The presence of elevated depressive symptoms and/or perceived stress was generally associated with increased waist circumference, higher CRP, and lower HDL. The combination of depressive symptoms and perceived stress, compared to either alone, was typically associated with poorer metabolic health outcomes. However, sociodemographic and lifestyle factors generally attenuated the associations between psychological factors and metabolic parameters. Conclusions: Elevated depressive symptoms in conjunction with high levels of perceived stress were more strongly associated with several parameters of metabolic health than only one of these psychological constructs in a large, diverse cohort of adults. Findings suggest that healthy lifestyle factors may attenuate the association between psychological distress and metabolic health impairment.