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Traumatic injuries represent a significant public health challenge, affecting millions worldwide annually and necessitating acute pain management that frequently involves the use of opioid analgesics to mitigate discomfort and facilitate recovery. Although opioids remain an integral part of post-traumatic injury pain management, their use exposes trauma survivors to the risk of developing persistent use, misuse, or opioid use disorder (OUD). Pre-injury health determinants, such as age, gender, psychiatric conditions, medical conditions, and substance use history, may interact with injury-related factors to acutely escalate the risk for misuse and addiction. Despite the growing recognition of these potential vulnerabilities, there remains a lack of evidence-based clinical decision support on modifiable and non-modifiable risk factors specific to post-traumatic injury opioid risk trajectories. This review summarizes the literature related to the multifactorial contributors to opioid misuse and addiction following traumatic injury such as patient-level (e.g., demographics, behavioral health), injury-related (e.g., severity, type), and system-level (e.g., prescribing patterns) characteristics. A comprehensive literature search, inclusive of the literature from 1995 to November 2025, was performed in PubMed/MEDLINE, Scopus, and Google Scholar using combinations of terms related to “opioids,” “misuse,” “addiction,” “trauma,” and “injury.” Search keywords and operators were developed in collaboration with a university librarian. Reference lists of articles were searched and synthesized. Case reports, case series, editorials, mini-reviews, letters to editor without original data, and qualitative studies were excluded. The findings of the review are expected to provide insight into clinical-decision making as it relates to the management of pain, pain-related distress and functional impact, and co-occurring conditions that may impact injury-related outcomes and the potential likelihood of substance misuse and addiction.