Down syndrome (DS) is the most common genetic alteration in humans, resulting from the trisomy of chromosome 21. Individuals with DS are characterized by physical traits and limitations related to intellectual functioning and the development of motor skills. People with DS tend to have lower levels of physical activity (PA) than the general population, despite its benefits for health and quality of life, which could be caused by barriers such as the lack of adapted programs or knowledge on how to adapt them. Therefore, this systematic review aimed to examine the impact of physical activity or sports programs on autonomy and quality of life in individuals with DS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to search four databases (Scopus, Web of Science, PubMed, and SportDiscus), adhering to the population, intervention, comparison, and outcome strategy. A total of 13 studies were selected that followed different training programs (combined training, adapted football, technology-based, pulmonary training, gymnastics and dance, water-based, and whole body vibration). Most of the interventions provided benefits for autonomy or quality of life (physical, psychological, cognitive, emotional, and social) in people with DS. In conclusion, the benefits of physical activity and sports programs adapted to people with DS are positive.