Abstract Background: DNA methylation and histone posttranslational modifications are epigenetics processes which contribute to neurophenotype of Down Syndrome (DS). Previous reports present strong evidence that nonhistone High mobility group N proteins (HMGN) are epigenetic regulators. They play important functions in several process to maintain the brain homeostasis. We aimed to analyze the differential expression of five human HMGN genes along some brain structures and age ranks from DS postmorten brain samples. Methodology: We performed a computational analysis of human HMGN expression from a DNA microarray experiment data (GEO database ID GSE59630). Using the transformed log2 data, we analyzed the differential expression of five HMGN genes in several brain areas associated with cognition in patients with DS. Moreover, using information from several genome databases, we explore the coexpression and protein interactions with the histones of nucleosome core particle and linker H1 histone. Results: We registered that HMGN1 and HMGN5 were significantly overexpressed in hippocampus and areas of prefrontal cortex including DFC, OFC and VFC of DS patients. Age ranks comparisons between euploid control and DS individuals showed that HMGN2 and HMGN4 were overexpressed in the DS brain of 16 to 22 weeks of gestation. From BioGRID database we registered high interaction scores of HMGN2 and HMGN4 with Hist1H1A and Hist1H2BA, Hist2AG, and Hist1H3A respectively. Conclusions: Overall our results give strong evidence to propose that DS would be an epigenetics-based aneuploidy. Remodeling the brain chromatin by HMGN1 and HMGN5 would essential pathway in the modification of brain homeostasis in DS.