Down syndrome (DS) is one of the most common chromosomal disorders. In addition to this variety of dysmorphic features. DS is also associated with a wide range of diseases and related comorbidities affecting different organs and systems. These comorbidities, together with societal and environmental influences, have a negative impact on physical activity in people with DS. Low levels of physical activity and energy expenditure have been identified as crucial players in worsening the acquisition of motor skills and executive functions. Executive functions are critical for the many skills (creativity, flexibility, self-control, and discipline) impacting our quality of life and make it possible to control impulses, mentally play with ideas, and stay focused. We proposed a broad overview of the available literature regarding motor skills and executive functions in pediatric patients with DS to understand the specific challenges for tailoring physical activity interventions. Motor skill interventions are effective in improving motor competence and performance on cognitive, emotional, and physical aspects in children with DS. Interventions based on executive functions in DS subjects are effective to contrast the cognitive decline and improve the everyday use of executive functions in youth and adults. Targeted interventions are mandatory for maximizing the benefits of physical activity, minimizing potential risks, and ultimately improving the overall health outcomes and quality of life for individuals with DS.