OBJECTIVES: To evaluate the efficacy of a mindfulness-based programme (MBP) for reducing stress in university students and its action mechanisms and to explore the capacity of virtual reality (VR) exposure to enhance adherence to the intervention. METHODS: This randomized controlled trial (RCT) involved assessment time points of baseline, posttreatment, and 6-month follow-up. A total of 280 students from two Spanish universities were randomly assigned to 'MBP', 'MBP + VR', or 'Relaxation' (active controls). Perceived stress posttreatment was the primary outcome; wellbeing and academic functional outcomes were assessed as well. Multilevel mixed-effects models were performed to estimate the efficacy of the programme. RESULTS: Both 'MBP' (B = -2.77, d = -0.72, p = .006) and 'MBP + VR' (B = -2.44, d = -0.59, p = .014) were superior to 'Relaxation' in improving stress, as well as most of the secondary outcomes, with medium-to-large effects posttreatment and at follow-up. The long-term effects of MBPs on stress were mediated by mindfulness and self-compassion in parallel. Treatment adherence was improved in the 'MBP + VR' group, with higher retention rates and session attendance (p < .001). CONCLUSIONS: This RCT supports the efficacy of an MBP compared to relaxation for reducing stress in university students through mindfulness and self-compassion as mechanisms of change. VR exposure may enhance treatment adherence. TRIAL REGISTRATION: ClinicalTrials.gov NCT03771300.