Aim: The present study aimed to determine whether youths with Down syndrome (DS) are able to increase lean mass and decrease fat mass, after 21 weeks of conditioning combined with a plyometric jumps training program. Methods: Twenty-six participants with DS (15 males) aged 10–19 years joined the study. Participants were divided into two comparable groups, exercise (EG; n = 13) and control (CG). Total and regional (trunk, upper and lower limbs) lean and fat masses were assessed by dual energy X-ray absorptiometry (DXA), at baseline and after the intervention. ANCOVA tests were used to evaluate differences between groups in pre- and post-training moments. Repeated measures of ANOVA adjusted by the increments in height and Tanner were applied to test the differences between pre and post-training moments. Adjusted percentages of change were calculated and differences between groups evaluated with Student's t test. Results: After the training period, EG showed an increase in total and lower limbs lean mass, while no changes in adiposity depots were observed. CG did not change neither the lean mass nor the fat mass except for decreased upper limbs fat mass (all p < 0.05) during the same period of time. As a result, time by exercise interactions were found for whole body and lower limbs lean mass (both p < 0.05). No differences in the percentage of fat were observed between groups at baseline or post-training. Overall, 21 weeks of conditioning combined with plyometric jumps training was an effective method for increasing lean mass in youths with DS; however, no changes in fat mass were observed.