Background: Unanticipated severe injury to part of the musculoskeletal system, referred to as orthopedic trauma, can be debilitating. It can also be accompanied by equally debilitating psychological distress, but little is known about the effective interventions for psychological sequelae of orthopedic trauma. Questions/Purposes: We sought to determine the effectiveness of interventions on psychological outcomes, such as post-traumatic stress disorder (PTSD), depression, and pain catastrophizing (feelings of helplessness, excessive rumination, and exaggerated description of pain), after major orthopedic trauma. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement as guidelines, we systematically searched Scopus, PubMed, and Google Scholar. Studies included for review were Englishlanguage interventional studies in an orthopedic trauma population that included assessment of post-injury psychological distress or disability as either a primary or secondary aim. Results: Twelve studies were identified, including six randomized trials, three prospective cohort studies, and three retrospective cohort studies. Study sample sizes ranged from 48 to 569 patients, the mean age ranged from 29 to 52.8 years, and the percentage of male patients ranged from 38 to 90%. We examined four categories of interventions. Peer group treatment (one study) significantly reduced rates of depression but had low participation rates. Brief interventions to teach coping and self-efficacy skills (two studies) decreased depression, pain catastrophizing, and anxiety scores while increasing self-efficacy on shortterm follow-up. Individualized counseling and rehabilitation (four studies) resulted in a consistent reduction in the risk of PTSD. Early amputation was found to result in lower rates of PSTD than limb salvage in US military personnel (four studies). One study examined surgeons' confidence in dealing with possible psychological distress; surgeons who participated in a program on collaborative care were significantly more confident that they could help their patients with such issues. Conclusion: Interventional strategies, including group interventions, brief individual interventions, longitudinal counseling, and consideration of early amputation in selected populations have proved effective in reducing negative psychological sequelae of major orthopedic trauma. Further research that determines the effects of interventions in this population is needed.