Background: The high prevalence of cognitive dysfunction is well documented in individuals with Down syndrome. However, only a few studies have focused on the effect of exercise on cognitive performance in this population. In particular, verbal fluency has been shown to be relevant to the early onset of Alzheimer's disease in individuals with Down syndrome. Thus, this study was aimed at investigating the relationship between acute exercise and verbal fluency in this population. Methods: It was a pre-post design. Twenty-eight participants (aged 14-31) were assigned to high-intensity exercise (i.e. 70-85% of predicted maximum heart rate) (N = 8), moderate-intensity exercise (i.e. 50-69% of predicted maximum heart rate) (N = 10) or attentional control (N = 10) groups. Two exercise groups walked on a treadmill using an incremental walking protocol, and the attentional control group watched a video for 20 min. Measures of verbal fluency (i.e. semantic fluency and phonetic fluency) were tested pre-intervention and post-intervention. Results: The result showed a quadric trend between semantic fluency and intensity of exercise. The improvement in cognitive performance on semantic fluency test was observed in the moderate-intensity exercise. However, neither a linear trend nor a quadric trend was seen in phonetic fluency. Conclusions: The result showed an inverted-U relationship between exercise intensity and semantic fluency. A larger sample size, testing time and more reliable psychophysiological measures (e.g. VO2max and neuroimaging technology), should be considered to explore the underlying mechanisms in this population.