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Serotonin (5-HT) is implicated in the reward processes underlying substance use disorder. Epigenetic and transcriptional mechanisms contribute to the development of addictive states. To examine the potential mechanisms of 5-HT receptor genes in opioid use disorder, we first determined the associations between several single-nucleotide polymorphism (SNPs) in three representative 5-HT receptor genes (HTR1B, HTR2A, and HTR3B) and susceptibility to heroin use disorder in 1731 participants. Gene–gene interactions among these genes were analyzed. After identifying the susceptibility genes and SNPs for heroin use disorder, DNA methylation in the promoter region of these susceptibility genes was compared between 111 healthy controls and 120 patients with heroin use disorder. In addition, associations between the susceptibility SNPs and methylation of the CpG sites and gene promoters with differential methylation between groups were examined. Finally, the function of the susceptibility SNPs in the expression of the corresponding genes was screened. Our results demonstrated that rs6296 in the HTR1B gene was correlated with susceptibility to heroin use disorder. Gene–gene interactions between the HTR1B and HTR2A genes were identified. The CpG sites HTR1B_07 and HTR1B_26 and the promoter region of the HTR1B gene were hypermethylated in patients with heroin use disorder compared with healthy controls. Notably, rs6296 correlated in an allele-specific manner with methylation in the HTR1B gene promoter in the blood and gene expression of the HTR1B gene in the frontal cortex and hypothalamus. SNP rs6296 was associated with opioid use disorder by involving mechanisms of DNA methylation and expression of the HTR1B gene. [ABSTRACT FROM AUTHOR]