Background: Lifestyle interventions like diet and exercise are commonly recommended for diabetes prevention, but it is unclear if depression modifies the likelihood of adherence. We evaluated the relationship between high depressive symptomatology and adherence to lifestyle interventions among patients with pre-diabetes.Methods: We conducted an analysis of the nationally representative National Health and Nutrition Examination Survey (NHANES) 2017–2018. Adults, aged ≥18 years old who were overweight or obese (BMI ≥25) and had diagnosed or undiagnosed pre-diabetes (HbA1c 5.7–6.4) were included. Depressive symptomatology was classified by the Patient Health Questionniare-9 (PHQ-9). We used self-reported adherence to physician suggested lifestyle changes of diet and exercise.Results: In this nationally representative survey of overweight or obese adults with pre-diabetes, 14.8% also have high depressive symptomatology. In unadjusted analyses, an interaction was observed with high depressive symptomatology acting as an effect modifier for adherence to exercise oriented interventions among patients with diagnosed pre-diabetes (p = 0.027). In logistic regressions, adjusting for age, sex, race, outpatient medical care in the past 12 months, and obesity, among patients with diagnosed pre-diabetes, depressed patients were less likely to attempt to exercise more (OR = 0.31; 95% CI: 0.10, 0.94) and no association between high depressive symptomatology and attempting to lose weight was observed (OR = 0.45; 95% CI: 0.14, 1.42).Conclusions: The findings of this nationally representative study of US adults, high depressive symptomatology decreases the likelihood of adherence to exercise based lifestyle recommendations among patients with diagnosed pre-diabetes.