This study examined whether exergames could improve physical, functional, and cognitive functions in people with Down syndrome. Twelve adults with DS, aged over 35 (M = 50.35, SD = 7.45), were randomly assigned to a Wii-based program (n = 6) or a control group (n = 6), and completed physical (Chair Stand Test, 6-Minute Walk Test), functional (TUG, TUDS), and cognitive tests (Corsi, Barrage tests). The experimental group completed a 12-week Wii-based program. There was high intervention adherence and, compared with the control group, greater improvements were observed in the Wii-based exercise intervention group in physical fitness and functional outcomes (p < 0.05), with no changes in cognitive outcomes.