Background: Down syndrome (DS) is the most common genetic disorder. To date, the scientific literature regarding micronutrient status in children and adolescents with DS has not been systematically reviewed. Therefore, our aim was to provide a systematic review and meta-analysis on this topic. Methods: We identified all relevant case-control studies published by 1 January 2022, by searching the PubMed and Scopus databases for original English-language articles analysing the micronutrient status of individuals with DS. Forty studies were included in the systematic review and 31 in the meta-analysis. Results: Statistically significant differences between individuals with DS (cases) and non-DS (controls) (P ≤ 0.05) were obtained for zinc, selenium, copper, vitamin B12, sodium and calcium. Serum, plasma and whole blood analyses showed lower zinc levels in cases than controls {standardised mean difference [SMD] serum [95% confidence interval (CI)] = -2.32 [-3.22, -1.41], P < 0.00001; SMD plasma [95% CI] = -1.29 [-2.26, -0.31], P < 0.01; SMD blood [95% CI] = -1.59 [-2.29, -0.89], P < 0.00001}. Similarly, plasma and blood selenium concentrations were significantly lower in cases than controls (SMD plasma [95% CI] = -1.39 [-2.26, -0.51], P = 0.002; SMD blood [95% CI] = -1.86 [-2.59, -1.13], P < 0.00001). Intraerythrocytic copper and serum B12 were higher in cases than controls (SMD Cu [95% CI] = 3.33 [2.19, 4.46], P < 0.00001; SMD B12 [95% CI] = 0.89 [0.01, 1.77], P = 0.048). Blood calcium was lower in cases than controls (SMD Ca [95% CI] = -0.77 [-1.34, -0.21], P = 0.007). Conclusions: This study provides the first systematic overview of micronutrient status in children and adolescents with DS and has shown that relatively little consistent research has been executed in this field. There is a clear need for more well-designed, clinical trials to study the micronutrient status and effects of dietary supplements in children and adolescents with DS.