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Background Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA sequencing was conducted on the dorsolateral prefrontal cortex and nucleus accumbens, regions heavily implicated in OUD, from postmortem brains in subjects with OUD. Methods We performed RNA sequencing on the dorsolateral prefrontal cortex and nucleus accumbens from unaffected comparison subjects (n = 20) and subjects diagnosed with OUD (n = 20). Our transcriptomic analyses identified differentially expressed transcripts and investigated the transcriptional coherence between brain regions using rank-rank hypergeometric orderlap. Weighted gene coexpression analyses identified OUD-specific modules and gene networks. Integrative analyses between differentially expressed transcripts and genome-wide association study datasets using linkage disequilibrium scores assessed the genetic liability of psychiatric-related phenotypes in OUD. Results Rank-rank hypergeometric overlap analyses revealed extensive overlap in transcripts between the dorsolateral prefrontal cortex and nucleus accumbens in OUD, related to synaptic remodeling and neuroinflammation. Identified transcripts were enriched for factors that control proinflammatory cytokine, chondroitin sulfate, and extracellular matrix signaling. Cell-type deconvolution implicated a role for microglia as a potential driver for opioid-induced neuroplasticity. Linkage disequilibrium score analysis suggested genetic liabilities for risky behavior, attention-deficit/hyperactivity disorder, and depression in subjects with OUD. Conclusions Overall, our findings suggest connections between the brain’s immune system and opioid dependence in the human brain.