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Background: Lifestyle risk behaviours typically emerge during adolescence, track into adulthood, and commonly co-occur. Interventions targeting multiple risk behaviours in adolescents have the potential to efficiently improve health outcomes, yet further evidence is required to determine their effect. We reviewed the effectiveness of eHealth school-based interventions targeting multiple lifestyle risk behaviours. Methods: In this systematic review and meta-analysis, we searched Ovid MEDLINE, Embase, PsycINFO, and the Cochrane Library databases between Jan 1, 2000, and March 14, 2019, with no language restrictions, for publications on school-based eHealth multiple health behaviour interventions in humans. We also screened the grey literature for unpublished data. Eligible studies were randomised controlled trials of eHealth (internet, computers, tablets, mobile technology, or tele-health) interventions targeting two or more of six behaviours of interest: alcohol use, smoking, diet, physical activity, sedentary behaviour, and sleep. Primary outcomes of interest were the prevention or reduction of unhealthy behaviours, or improvement in healthy behaviours of the six behaviours. Outcomes were summarised in a narrative synthesis and combined using random-effects meta-analysis. This systematic review is registered with PROSPERO, identifier CRD42017072163. Findings: Of 10 571 identified records, 22 publications assessing 16 interventions were included, comprising 18 873 students, of whom on average 56·2% were female, with a mean age of 13·41 years (SD 1·52). eHealth school-based multiple health behaviour change interventions significantly increased fruit and vegetable intake (standard mean difference 0·11, 95% CI 0·03 to 0·19; p=0·007) and both accelerometer-measured (0·33, 0·05 to 0·61; p=0·02) and self-reported (0·14, 0·05 to 0·23; p=0·003) physical activity, and reduced screen time (−0·09, −0·17 to −0·01; p=0·03) immediately after the intervention; however, these effect