A crossover experiment was performed to determine whether age and sex, or their interaction, affect the impact of acute aerobic exercise on vigor-activity (VA). We also tested whether changes in VA mediated exercise effects on performance on various cognitive tasks. Sixty-eight physically inactive volunteers participated in exercise and TV-watching control conditions. They completed the VA subscale of the Profile of Mood States immediately before and 2 min after the intervention in each condition. They also performed the Trail Making Test 3 min after the intervention in each condition. Statistical analyses produced a condition × age × sex interaction characterized by a higher mean VA gain value in the exercise condition (compared with the VA gain value in the TV-watching condition) for young female participants only. In addition, the mediational analyses revealed that changes in VA fully mediated the effects of exercise on TMT-Part A performance.