OBJECTIVES: Acute orthopedic traumatic musculoskeletal injuries are prevalent, costly, and often lead to persistent pain and functional limitations. Psychological risk factors (eg, pain catastrophizing and anxiety) exacerbate these outcomes but are often overlooked in acute orthopedic care. Addressing gaps in current treatment approaches, this mixed-methods pilot study explored the use of a therapeutic virtual reality (VR; RelieVRx ), integrating principles of mindfulness and cognitive-behavioral therapy, for pain self-management at home following orthopedic injury. METHODS: We enrolled 10 adults with acute orthopedic injuries and elevated pain catastrophizing or pain anxiety from Level 1 Trauma Clinics within the Mass General Brigham health care system. Participants completed daily RelieVRx sessions at home for 8 weeks, which included pain education, relaxation, mindfulness, games, and dynamic breathing biofeedback. Primary outcomes were a priori feasibility, appropriateness, acceptability, satisfaction, and safety. Secondary outcomes were pre-post measures of pain, physical function, sleep, depression, and hypothesized mechanisms (pain self-efficacy, mindfulness, and coping). RESULTS: The VR and study procedures met or exceeded all benchmarks. We observed preliminary improvements in pain, physical functioning, sleep, depression, and mechanisms. Qualitative exit interviews confirmed high satisfaction with RelieVRx and yielded recommendations for promoting VR-based trials with orthopedic patients. DISCUSSION: The results support a larger randomized clinical trial of RelieVRx versus a sham placebo control to replicate the findings and explore mechanisms. There is potential for self-guided VR to promote evidence-based pain management strategies and address the critical mental health care gap for patients following acute orthopedic injuries.