Background Given that ‘digitally native’ children and young people spend much time at school, universal e-mental health interventions (ueMHIs) may have a role in supporting their wellbeing and reducing common mental health problems like anxiety and depression. However, the efficacy of school-based ueMHIs has never formally been evaluated. Methods During this systematic review and meta-analysis, we searched online databases MEDLINE, ERIC and ACM and the grey literature for trials of school-based ueMHIs targeted at improving wellbeing or reducing anxiety or depression in students aged 5–18. Primary outcomes were changes in symptoms of wellbeing, anxiety and depression at <3 months. Secondary outcomes were changes in these symptoms at 3–12 months and >12 months. Meta-analysis was conducted using a random effects model. Quality of included studies was appraised using the Cochrane risk of bias (RoB) tool. This study was registered with PROSPERO, CRD42023421872. Findings From 11,026 screened records, 15 papers were found and included in a systematic review. Of these, 14 papers including 8844 students were analysed in the meta-analysis. School-based ueMHIs did not significantly reduce anxiety (SMD = −0.55, 95% CI −1.68, 0.59) or depression (SMD = −0.29, 95% CI = −0.89, 0.32) at <3 months. School-based ueMHIs also did not significantly reduce anxiety (SMD = −1.03, 95% CI −3.20, 1.14) or depression (SMD = −0.47, 95% CI −1.40, 0.46) at 3–12 months. School-based ueMHIs did not significantly improve wellbeing at <3 months (SMD = 0.01, 95% CI −0.12, 0.14) and favoured control condition at 3–12 months (SMD = −0.14, 95% CI −0.23, −0.05). RoB was high across most studies and the overall quality of evidence was very low. Interpretation Although existing school-based ueMHIs show promise for addressing pupil mental health concerns, further higher-quality evidence is needed. There is room for the development of new school-based ueMHIs for reducing pupil anxiety and depression and improving wellbeing in a scalable, clinically and cost-effective manner, whilst not causing harm.