This systematic review examined whether physical activity interventions improve health outcomes in adults with Down syndrome (DS). We searched PubMed, APA PsycInfo, SPORTDiscus, APA PsycARTICLES, and Psychology and Behavioral Sciences Collection using keywords related to DS and physical activity. We included 35 studies published in English since January 1, 1990. Modes of exercise training programs included aerobic exercise, strength training, combined aerobic and strength training, aquatic, sport and gaming, and aerobic and strength exercise interventions combined with health education. The evidence base indicates that aerobic and strength exercise training improve physical fitness variables including maximal oxygen uptake, maximal heart rate, upper and lower body strength, body weight, and body fat percentage. Sport and gaming interventions improve functional mobility, work task performance, and sport skill performance. We concluded that adults with DS can accrue health benefits from properly designed physical activity and exercise interventions.