Objective: What effect does regular exercise have on oxidative stress in people with Down syndrome? Design: Systematic review with meta-analyses. Methods: A systematic review with meta-analyses was conducted. Six databases were searched from inception until August 2017. Studies where included if participants with Down syndrome (any age) had completed an exercise program of at least 6 weeks duration and at least one biomarker measured the generation or removal of reactive oxidative species. Data were extracted using a customised form. Risk of bias was assessed using the Cochrane Collaboration's Risk of Bias assessment tool. Effect sizes were calculated and meta-analyses completed for clinically homogeneous data using a random effects model. Results: Seven studies (11 articles) involving 144 inactive participants investigated the effect of moderate intensity aerobic exercise. No pattern emerged for how most biomarkers responded with non-significant pooled effect sizes and high levels of heterogeneity observed. The exception was catalase which increased significantly after exercise (standardised mean difference 0.39, 95%CI 0.04–0.75; I2 15%). Available studies were at high risk of bias. Two of five studies that measured more than one biomarker reported a decrease in oxidative stress with increased antioxidant activity after exercise but the other three (including one small randomised controlled trial) reported increased oxidative stress with variable change in antioxidant activity. Conclusions: There remains uncertainty about the effect of exercise on oxidative stress in people with Down syndrome. Review registration: PROSPERO CRD42016048492.