Objective <p>This systematic review and meta-analysis aimed to evaluate the overall efficacy of virtual reality-based exercise interventions (VR-EXIs) in alleviating depression and to provide evidence supporting the application of innovative non-pharmacological approaches in nursing practice.</p> Methods <p>We conducted a systematic literature search across six electronic databases from inception to May 2025. Two independent researchers followed established inclusion and exclusion criteria to identify relevant randomized controlled trials (RCTs). Risk of bias assessment was conducted using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Standardized mean differences (SMDs; Hedges’ g) with 95% confidence intervals (CIs) were utilized to pool the effect sizes. We conducted moderator analysis to explore sources of heterogeneity and performed sensitivity analysis to assess the robustness of the pooled results. Publication bias was evaluated by visually inspecting funnel plots and performing Egger’s test. We evaluated the certainty of evidence for the pooled results according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines. This systematic review and meta-analysis were registered in PROSPERO (registration number: CRD420251150311).</p> Results <p>The systematic review included 19 RCTs involving 1,275 participants, of which 12 were pooled in the meta-analysis. The included studies exhibited considerable heterogeneity in terms of population characteristics and intervention implementation. The included studies ranged in quality from low to high risk of bias. The pairwise meta-analysis indicated that, compared with the control groups, VR-EXIs significantly improved depression (SMD = -0.79, 95% CI [-1.28, -0.29], p &lt; 0.01). The meta-regression analysis indicated that sociodemographic characteristics and implementation parameters exerted no impact on the efficacy of VR-EXIs. The subgroup analysis indicated that the efficacy of VR-EXIs on depression showed significant differences under different control conditions and disease status. The sensitivity analysis indicated that the pooled results of VR-EXIs on depression were robust, with effect sizes ranging from − 0.89 to -0.55. However, according to the GRADE criteria, the certainty of evidence for the efficacy of VR-EXIs in alleviating depression remains very low.</p> Conclusion <p>Our findings support the positive effects of VR-EXIs in alleviating depression. However, this evidence may exhibit heterogeneity owing to differences in population characteristics and intervention implementation, and the certainty of evidence is very low. Future research should be grounded in a more comprehensive population and intervention information to address this study’s limitations.</p> Clinical trial number <p>Not applicable.</p>