Elucidating the impact of epigenetic modifications in the evolution of phenotypes remains as a fundamental yet unresolved question in biology. In particular, the role of epigenetic divergence on the evolution of human brains, which underwent an unparalleled degree of recent evolutionary innovation, may have deep implications for human cognition and neuropsychiatric diseases. Systematic analyses employing unbiased epigenome-wide methods, and including outgroup species and large panel of individuals are needed to fully understand the role of epigenetic divergence on human brain evolution. Here we report comprehensive identification and analyses of differentially methylated regions (DMRs) in human brains. We used comparative whole genome bisulfite sequencing (WGBS) of human, chimpanzee and rhesus macaque prefrontal cortices (n=8), unbiased non-parametric tests, as well as targeted deep genomic and bisulfite sequencing in an independent panel of 37 individuals across six primate species. We identify 278 DMRs using conservative cutoffs. These DMRs conspicuously co-localize with functional genomic indicators of transcriptional regulation, including chromatin features and transcription factor binding profiles. In particular, we identify many loci annotated as intergenic yet exhibiting conspicuous chromatin signatures of active transcription in brains, indicating that they represent currently unannotated loci of human brain-specific transcription. Remarkably, a large number of DMRs are found in a spatially clustered manner and tend to participate in active chromatin loops, indicating evolutionary remodeling at the higher-order chromatin structure. Analyses of previously generated gene expression and epigenetic data also support a role of DMRs in regulation of transcription. In summary, we identify hundreds of human brain specific DMRs and demonstrate that the unique epigenetic profiles of the human brain are supported in a large number of samples across multiple species. We unravel human brain specific epigenetic changes at regulatory regions that shape gene expression divergence. Substantial reprogramming of the epigenomic landscape appears to contribute to the evolutionary specializations in our brains.