Understanding the neuroplastic capacity of people with Down syndrome (PwDS) can potentially reveal the causal relationship between aberrant brain organization and phenotypic characteristics. We used resting-state EEG recordings to identify how a neuroplasticity-triggering training protocol relates to changes in the functional connectivity of the brain’s intrinsic cortical networks. Brain activity of 12 PwDS before and after a 10-week protocol of combined physical and cognitive training was statistically compared to quantify changes in directed functional connectivity in conjunction with psychosomatometric assessments. PwDS showed increased connectivity within the left hemisphere and from left-to-right hemisphere, as well as increased physical and cognitive performance. Our findings reveal a strong adaptive neuroplastic reorganization as a result of the training that leads to a less-random network with a more pronounced hierarchical organization. Our results go beyond previous findings by indicating a transition to a healthier, more efficient, and flexible network architecture, with improved integration and segregation abilities in the brain of PwDS. Resting-state electrophysiological brain activity is used here for the first time to display meaningful relationships to underlying Down syndrome processes and outcomes of importance in a translational inquiry. This trial is registered with Identifier NCT04390321. The effects of cognitive and physical training on the neuroplasticity attributes of people with and without cognitive impairment have been well documented via neurophysiological evaluations and network science indices. However, there is still insufficient evidence for people with Down syndrome (PwDS). We investigated the effects of a combinational training protocol on the brain network organization of 12 adult PwDS by using EEG and network indices coupled with tests assessing their cognitive and physical capacity. We report evidence of adaptational neuroplastic effects, pointing to a transitional state toward a healthier organization with an increased ability to integrate and segregate information. Our findings underline the ability of the Down syndrome brain to respond to the cognitive demands of external stimuli, reflecting the possibility of developing independent-living skills.