Individuals with Down syndrome (DS) have a higher prevalence of obesity than the general population. This has traditionally been attributed to endocrine issues and deficient exercise. However, the development of obesity is coupled with deficits in neural reward responses, and previous works showed dopaminergic disturbances in DS. We here tested the hypothesis that “hedonic” overeating may play a central role in the development of obesity as a consequence of sub-functional dopaminergic neurotransmission in a mouse model that bears in triplicate many most of the genes in trisomy 21, Ts65Dn. Meal pattern analysis in this trisomic mouse model (Ts65Dn), revealed an increased preference for energy-dense food. Trisomic mice also scored significantly higher in compulsivity and inflexibility tests as measured by limited access to energy-dense food and food adulteration with quinine hydrochloride. We detected reduced dopamine levels in the prefrontal cortex of Ts65Dn mice, and insensitivity to the dopamine D2receptor agonist (quinpirole) anorectic effect for palatable foods that may facilitate overeating in an attempt to restore optimal dopamine levels. Interestingly, impulsive and compulsive behaviors were significantly reduced when prelimbic-to-nucleus accumbens projections were activated in Ts65Dn mice using a chemogenetic approach. Our work unravels a new mechanism underlying vulnerability to the development of overeating in DS, which could pave the way towards novel and efficient interventions for obesity.