Down syndrome (DS), caused by the triplication of human chromosome 21, is the most frequent genetic cause of mental retardation. The Ts65Dn mouse model of DS show many neurological similarities to the human syndrome, including decreased hippocampal neurogenesis and cognitive impairment. In this study, we have investigated the effect of aerobic physical exercise on adult neurogenesis, synaptic plasticity and memory in Ts65Dn mice. Exposure of adult Ts65Dn mice to running wheels for one month increased the proliferation of neuronal precursor cell and stimulated adult neurogenesis in the hippocampal dentate gyrus. Moreover, physical exercise promoted the recovery of hippocampal synaptic plasticity and, most importantly, fully restored learning and memory in different behavioral task in trisomic mice. These findings demonstrate that Ts65Dn mice benefit from voluntary wheel running and provide evidence that physical exercise could represent a valuable complementary therapy for pharmacological interventions aimed at rescuing cognitive disabilities in DS patients.