Background: The benefits of weight loss programs on mood, cognitive, and motor behavior are largely limited to those of calorie restriction or exercise alone. Our aim was to investigate the effect of combined calorie restriction and aerobic exercise intervention on mood, brain activity, and cognitive and motor behavior in overweight and obese women. Methods: Participants aged 36–56 years were randomized to either a control or an experimental group (aerobic exercise + 12.5% energy intake reduction) for a 6-month period. Changes in brain-derived neurotrophic factor levels, mood, prefrontal cortex activity, cognitive and motor performance were assessed. Results: Confusion and depression increased in the control group ( P < .05), whereas tension decreased in the experimental group ( P < .05). Brain-derived neurotrophic factor level and learning of a speed–accuracy task remained unchanged. Although prefrontal cortex activity and executive functions were not affected, the reaction time of visual scanning and associative learning were improved in the experimental group ( P < .05). An improvement in reaction time during the speed–accuracy task was observed ( P < .05). Conclusion: Combined calorie restriction and aerobic exercise intervention improved the psychosocial state, had little impact on cognition, and no effect on brain activity and learning of the speed–accuracy task.