To study the influence of aerobic exercise training on brain-derived neurotrophic factor (BDNF), insulin resistance, and lipid profile in middle-aged men diagnosed with metabolic syndrome (MetS). This is an experimental repeated measure study. Subjects participated in aerobic training programs (18 sessions of 25-40 minutes per session) in Guilan University gymnasium and court. A total of 21 middle-aged men (50-65 years old) diagnosed with MetS participated. We randomly divided 21 middle-aged men with MetS into exercise and control groups. The exercise group followed an aerobic training program (18 sessions, 3/wk) at 50% to 60% of V[Combining Dot Above]O2 peak (25-40 minutes per session) and 6 weeks of detraining. Blood samples were collected at baseline, end of the training, and detraining. High BDNF level in patients with MetS and its reduction after chronic aerobic exercise. Aerobic training significantly decreased all the metabolic risk factors, including overall MetS z score, insulin resistance, and lipid profile (P < 0.05). After the detraining period, plasma triglyceride, high-density lipoprotein, and also overall MetS z score remained unchanged (P < 0.05); however, serum BDNF, which was decreased by aerobic training (P = 0.013), restored to the baseline at the end of the detraining (P = 0.018). Improved metabolic risk factors along with decreased serum BDNF in response to aerobic training and the opposite direction during the detraining emphasize the importance of physical activity in the treatment of MetS and prevention of related diseases.