Short tandem repeats (STRs), characterized by high-copy number mutations, represent one of the fastest-evolving genomic elements. However, human-specific expanded STRs (heSTRs) have lacked comprehensive genome-wide characterization. Leveraging 148 human and 26 nonhuman primate haploid genomes, we identified 8813 heSTRs with robust expansions in copy number distributions. Our analysis revealed notable associations between heSTRs and brain- and neuron-specific distal regulatory signals. Potential target genes regulated by heSTRs, identified by incorporating distal regulations, are enriched with neuronal development-related functions and disorders, displaying neuron-specific expression enhancement in humans. Moreover, heSTRs are associated with enhanced chromatin accessibility specifically in human neurons. In addition, heSTRs show substantial association with pathogenic STR loci exhibiting abnormal copy number variations, as reported by cohort studies on schizophrenia and autism. This study underscores the role of heSTRs in both human evolution and disorders, offering valuable insights for future research on STRs from an evolutionary perspective.