Background: Reports of positive effects of aerobic exercise on cognitive function in persons with Down syndrome are extremely limited. However, a novel exercise intervention, termed assisted cycling therapy (ACT), has resulted in acutely improved cognitive planning ability and reaction times as well as improved cognitive planning after 8 weeks of ACT in adolescents and young adults with Down syndrome. Here, we report the effects of 8 weeks of ACT on reaction time, set-shifting, inhibition and language fluency in adolescents with Down syndrome. Methods: Adolescents with Down syndrome (age: ~18 years) were randomly assigned to 8 weeks of ACT (n = 17) or voluntary cycling (VC: n = 16), and a convenience sample (n = 11) was assigned to be an inactive comparison group (NC: n = 11). During ACT, the cycling cadence of the participants was augmented to an average cadence that was 80% faster than the voluntary cadence of the VC group. The increase in cadence was achieved with an electric motor in the stationary bicycle. Reaction time, set-shifting, inhibition and language fluency were assessed before and after 8 weeks of intervention. Results: Power output and heart rates of the ACT and VC groups were almost identical, but the ACT cadence was significantly faster. The ACT group, but not the VC or NC groups, showed significantly improved reactions times (Hedges' g = -0.42) and inhibitory control (g = 0.18). Only the VC group showed improved set-shifting ability (g = 0.57). The ACT and VC groups displayed improved semantic language fluency (g = 0.25, g = 0.22, respectively). Discussions: These and previous results support the hypothesis of increased neuroplasticity and prefrontal cortex function following ACT and, to a smaller extent, following VC. Both ACT and VC appear to be associated with cortical benefits, but based on current and previous results, ACT seems to maximize the benefits.