Opioid misuse and opioid-involved overdose deaths are a massive public health problem involving the intertwined misuse of prescription opioids for pain management with the emergence of extremely potent fentanyl derivatives, sold as standalone products or adulterants in counterfeit prescription opioids or heroin. The incidence of repeated opioid overdose events indicates a problematic use pattern consistent with the development of the medical condition of opioid use disorder (OUD). Prescription and illicit opioids reduce pain perception by activating µ-opioid receptors (MOR) localized to the central nervous system (CNS). Dysregulation of meso-corticolimbic circuitry that subserves reward and adaptive behaviors is fundamentally involved in the progressive behavioral changes that promote and are consequent to OUD. Although opioid-induced analgesia and the rewarding effects of abused opioids are primarily mediated through MOR activation, serotonin (5-HT) is an important contributor to the pharmacology of opioid abused drugs (including heroin and prescription opioids) and OUD. There is a recent resurgence of interest into psychedelic compounds that act primarily through the 5-HT_2A receptor (5-HT_2AR) as a new frontier in combatting such diseases (e.g., depression, anxiety, and substance use disorders). Emerging data suggest that the MOR and 5-HT_2AR crosstalk at the cellular level and within key nodes of OUD circuitry, highlighting a major opportunity for novel pharmacological intervention for OUD. There is an important gap in the preclinical profiling of psychedelic 5-HT_2AR agonists in OUD models. Further, as these molecules carry risks, additional analyses of the profiles of non-hallucinogenic 5-HT_2AR agonists and/or 5-HT_2AR positive allosteric modulators may provide a new pathway for 5-HT_2AR therapeutics. In this review, we discuss the opportunities and challenges associated with utilizing 5-HT_2AR agonists as therapeutics for OUD.