Background Metabolic syndrome components—waist circumference, high‐density lipoprotein cholesterol (HDL‐C), triglycerides, systolic blood pressure and fasting glucose—are cross‐sectionally associated with depression and anxiety with differing strength. Few studies examine the relationships over time or whether antidepressants have independent effects. Methods Participants were from the Netherlands Study of Depression and Anxiety (NESDA; N = 2,776; 18–65 years; 66% female). At baseline, 2‐ and 6‐year follow‐up, participants completed diagnostic interviews, depression and anxiety symptom inventories, antidepressant use assessment, and measurements of the five metabolic syndrome components. Data were analyzed for the consistency of associations between psychopathology indicators and metabolic syndrome components across the three assessment waves, and whether psychopathology or antidepressant use at one assessment predicts metabolic dysregulation at the next and vice versa. Results Consistently across waves, psychopathology was associated with generally poorer values of metabolic syndrome components, particularly waist circumference and triglycerides. Stronger associations were observed for psychopathology symptom severity than diagnosis. Antidepressant use was independently associated with higher waist circumference, triglycerides and number of metabolic syndrome abnormalities, and lower HDL‐C. Symptom severity and antidepressant use were associated with subsequently increased number of abnormalities, waist circumference, and glucose after 2 but not 4 years. Conversely, there was little evidence that metabolic syndrome components were associated with subsequent psychopathology outcomes. Conclusions Symptom severity and antidepressant use were independently associated with metabolic dysregulation consistently over time and also had negative consequences for short‐term metabolic health. This is of concern given the chronicity of depression and anxiety and prevalence of antidepressant treatment.