Recent studies have emphasized that regular exercise should be encouraged as a key part of care and support for people with Down syndrome (DS). However, muscle hypotonia has traditionally been considered a major barrier to resistance training (RT) in people with DS. The main objective of this study was to analyze the impact of circuit RT on markers of muscle damage. The secondary objective was to assess the influence of a RT program on body composition and work task performance. Thirty-six men with DS were recruited and randomly assigned to perform a circuit RT program with six stations 3 days/week for 12 weeks (n = 18) or to a control group (n = 18). Body composition was assessed by bioelectrical impedance analysis. Serum markers of muscle damage (creatine kinase, myoglobin, and lactate dehydrogenase) were determined at baseline and at the end of training weeks 1, 6, and 12. Work task performance was assessed using the weighted pail-carry test. RT did not induce significant changes in markers of muscle damage during the intervention. Furthermore, muscle mass and work task performance were significantly improved in the exercise group. These findings suggest that circuit RT can be used safely to increase muscle mass and work task performance in young adults with DS. Muscle hypotonia should not be considered a major barrier to exercise in people with DS, provided that qualified staff design and supervise all training sessions.