Patients with breast cancer endure high levels of psychological and physical pain. Virtual reality (VR) may be an acceptable, safe intervention to alleviate the negative emotions and pain of patients with cancer We aimed to test the long-term effects of VR on psychological distress and quality of life (QOL) with traditional care in Chinese patients with breast cancer. We also explored the intervention mechanism and the acceptability of VR A total of 327 eligible participants were randomly assigned to a VR intervention group or a control group. The Distress Thermometer, QLQ-C30 (Quality of Life Questionnaire version 3.0), and Virtual Reality Symptom Questionnaire were assessed at baseline, postintervention (3 mo), and follow-up (6 mo). Analysis followed the intention-to-treat (ITT) principle. The generalized estimating equations model was used to analyze the longitudinal data, and the PROCESS macro was used to analyze the mediating effect. Compared with the control group, patients with breast cancer in the VR group had lower distress scores (P=.007), and higher health-related QOL scores (physical, role, emotional, cognitive, and social functioning) after 6 months (P<.05). Psychological distress had mediating effects on the longitudinal association between VR and the health-related QOL (indirect effect=4.572‐6.672, all P<.05). VR intervention technology may help reduce distress and improve QOL for patients with breast cancer over time. By incorporating a mediating analysis, we showed that the QOL benefits of VR intervention was manifested through positive effects on psychological distress risk factors Chinese Clinical Trial Registry ChiCTR2000035049; https://www.chictr.org.cn/showproj.html?proj=53648