While opioid prescribing rates have drawn researchers' attention, little is known about the mechanisms through which income inequality affects opioid prescribing rates and even less focuses on whether there is a rural/urban difference in mediating pathways. Applying mediation analysis techniques to a unique ZIP code level dataset from several sources maintained by the Centers for Medicare and Medicaid Services, we explicitly examine two mechanisms through residential stability and social isolation by rural/urban status and find that (1) income inequality is not directly related to opioid prescribing rates, but it exerts its influence on opioid prescribing via poor residential stability and elevated social isolation; (2) social isolation accounts for two-thirds of the mediating effect of income inequality on opioid prescribing rates among urban ZIP codes, but the proportion halves among rural ZIP codes; (3) residential stability plays a larger role in understanding how income inequality matters in rural than in urban ZIP codes; and (4) beneficiary characteristics only matter in urban ZIP codes. These findings offer nuanced insight into how income inequality affects opioid prescribing rates and suggests that the determinants of opioid prescribing rates vary by rural/urban status. Future research may benefit from identifying place-specific factors for opioid prescribing rates.