Methadone is a synthetic opioid with unique characteristics that make it an effective treatment option for both chronic pain and opioid use disorder (OUD). While it functions similarly to other opioids by acting as a full mu-opioid receptor agonist, methadone offers additional benefits related to NMDA receptor antagonism properties. This dual mechanism makes it particularly useful for treating neuropathic pain and potentially reducing opioid tolerance. Methadone pharmacokinetics is complex, with a long half-life and high lipophilicity that not only contribute to prolonged pain relief but also pose challenges, including the risk of drug accumulation and toxicity. It is metabolized by various CYP enzymes, and an individual’s genetic variations can affect its breakdown, leading to significant variability in how different patients process the drug. Methadone is widely used in OUD treatment through opioid substitution therapy, helping to stabilize patients by reducing cravings and preventing relapse. Despite its many clinical benefits, methadone requires careful monitoring related to potential side effects, e.g., respiratory depression and QT interval prolongation. In this regard, guidelines require an initial EKG to determine whether methadone will be safe in each patient, with those having a QT prolongation greater than 450 ms being at risk for torsades de pointes. When used appropriately, methadone is a cost-effective and powerful tool for managing both chronic pain and opioid dependence, offering significant advantages over other opioids in specific contexts. In this chapter, we explore methadone pharmacology, indications, dosing, and administration. Additionally, discussion on efficacy in chronic pain management, side effect profile, and clinical role in OUD and pain management is reviewed.