Background Obesity is a major health problem in people with intellectual disabilities. It is also widely accepted that low‐grade systemic inflammation associated to obesity plays a key role in the pathogenic mechanism of several disorders. Fortunately, physical activity has shown to improve inflammation in people with metabolic syndrome and type 2 diabetes. Accordingly, we assessed the influence of aerobic training on pro‐inflammatory cytokines and acute phase proteins in women with Down syndrome. Methods To achieve this outcome, 20 premenopausal obese young women with Down syndrome volunteered for this study. Eleven were randomly assigned to the intervention group and performed a 10‐week aerobic training programme, three sessions per week, consisting of a warm‐up then a 30‐ to 40‐min treadmill exercise at a work intensity of 55–65% of peak heart rate followed by a cooling‐down period. The control group included nine age‐, sex‐ and body mass index‐matched women with Down syndrome. Fat mass percentage and fat distribution were measured. Plasmatic levels of tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and fibrinogen were assessed by commercial enzyme‐linked immunosorbent assay kits. C‐reactive protein (CRP) was assessed by nephelometry. Results Plasmatic levels of TNF‐α (11.7 ± 1.6 vs. 9.2 ± 1.3 pg/ml; P = 0.022), IL‐6 (8.2 ± 1.1 vs. 6.1 ± 0.9 pg/ml; P = 0.014) and high sensitive CRP (0.62 ± 0.11 vs. 0.53 ± 0.09 mg/dl; P = 0.009) were significantly reduced in the intervention group. Further, significant correlations between plasmatic and anthropometric parameters were found. Conclusion A 10‐week training programme reduced pro‐inflammatory cytokines and acute phase proteins in obese young women with Down syndrome. Long‐term, well‐conducted studies are still required to determine whether correction of this low‐grade inflammation improves clinical outcomes of women with trisomy 21.