Abstract Background Therapeutic exercise exerts positive effects by mitigating or reducing the motor or cognitive changes that people with Down syndrome undergo throughout their life. There are no updated systematic reviews that integrate the evidence available in way that facilitates decision-making for physical rehabilitation teams. This study aimed to assess the effect of different types of physical exercise on the motor function of adults with Down syndrome. Methods We conducted a systematic review and meta-analysis of randomized clinical trials and quasi-experimental studies. The literature search was performed between September 2020 and June 2021 using the PubMed, SCIELO, Epistemonikos, and Lilacs databases. Studies were selected according to pre-determined inclusion and exclusion criteria. The risk-of-bias assessment was performed using the risk-of-bias rating tool. Risk-of-bias assessment and meta-analyses were performed using the RevMan software package. Results Water aerobic exercise significantly increased isometric push-up strength time (mean difference MD = 24.00 [95% CI = 2.66–45.35]; P = 0.03), while combined exercise significantly increased muscle strength both in the upper limbs (MD = 11.93 [95% CI = 4.72–19.14]; P = 0.001) and lower limbs (MD = 18.47 [95% CI = 2.34–34.60]; P = 0.02). Aerobic exercise improved spatiotemporal gait parameters. Aerobic exercise in an aquatic environment and continuous and interval training improved six-minute walk (MD = 43.21 [95% CI = 0.84–85.57]; P = 0.05). The certainty assessment revealed low certainty for all outcomes. Conclusions There was low certainty of evidence for the outcomes proposed in this review. However, therapeutic exercise was shown to be effective in improving muscle strength and gait functionality.