Background: Opioid use disorder (OUD) vulnerability, progression, and course are driven by biological, developmental, environmental, and genetic factors. Single nucleotide polymorphisms (SNPs) in opioid receptor (OPR) genes can influence receptor expression, structure, or function, potentially altering OUD susceptibility and impacting treatment response and relapse rates. Delta receptors 1 (OPRD1), kappa receptors 1 (OPRK1), and mu receptors 1 (OPRM1) are commonly studied OUD-related genes. They were examined in different ethnic groups, and their results conflicted. Therefore, this research aimed to determine the impact of sociodemographic and genetic factors on OUD risk in a sample of Egyptians. It fills a crucial gap in understanding the effect of SNPs within OPR genes on OUD among Egyptians. Methods: This case-control study evaluated 50 opioid substance users versus 50 healthy, age- and sex-matched non-substance users. The sociodemographic profiles and opioid use data were collected from medical records and semi-structured interviews. Participants were assessed through the DSM-5 and ICD-11 Symptom Checklist. The SNPs in T921C of OPRD1, G36T of OPRK1, and A118G of OPRM1 genes were adopted. Venous blood samples were collected for DNA extraction and gene SNPs were examined after PCR amplification under an ultraviolet transilluminator. Results: The OUD group exhibited polymorphisms in OPRD1 (2 %), OPRK1 (10 %), and OPRM1 (2 %) with no significant associations between SNPs and OUD. Multivariable regression analysis identified important OUD risk factors, including low education levels and a positive family history of SU. They were associated with an increased likelihood of OUD with 8 and 6 times, respectively. Conclusion: This study provides initial evidence suggesting that OUD susceptibility among Egyptians is mainly related to sociodemographic factors rather than genetic polymorphisms in OPR genes. Pre-university education, including illiterate participants, as well as participants with primary and secondary education, increased OUD susceptibility risk >8 times (P value < 0.001, adjusted odds ratio 8.652 with 95 % confidence interval). A positive family history of SU was linked with increased susceptibility by more than sixfold (P value 0.029, adjusted odds ratio 6.101 with 95 % confidence interval).