© 2019 The Author(s). Background: Illicit substance misuse is a growing public health problem, with misuse peaking among 18-25 year-olds, and attendance at third-level education identified as a risk factor. Illicit substance misuse has the potential to harm mental and physical health, social relationships, and impact on academic achievements and future career prospects. Digital interventions have been identified as a vehicle for reaching large student populations and circumventing the limited capacity of student health services for delivering face-to-face interventions. Digital interventions have been developed in the area of alcohol and tobacco harm reduction, reporting some effectiveness, but the evidence for the effectiveness of digital interventions targeting illicit substance misuse is lacking. This review aims to systematically identify and critically appraise studies examining the effectiveness of digital interventions for illicit substance misuse harm reduction in third-level students. Methods: We systematically searched ten databases in April 2018 using keywords and database specific terms under the pillars of "mHealth," "substance misuse," and "student." To be eligible for inclusion, papers had to present a measure of illicit substance misuse harm reduction. Included articles were critically appraised and included in the qualitative synthesis regardless of quality. Results: A total of eight studies were included in the qualitative synthesis. Studies reported harm reduction in terms of substance misuse or initiation, as consequences or problems associated with substance misuse, or as correction of perceived social norms. Overall, five out of the eight studies reported at least one positive outcome for harm reduction. The critical appraisal indicated that the study quality was generally weak, predominantly due to a lack of blinding of study participants, and the use of self-reported substance misuse measures. However, results suggest that digital interventions may produce a modest reduction in harm from illicit substance misuse. Conclusions: The results of this review are positive, and support the need for further high-quality research in this area, particularly given the success of digital interventions for alcohol and tobacco harm reduction. However, very few studies focused solely on illicit substances, and those that did targeted only marijuana. This suggests the need for further research on the effectiveness of this type of intervention for other illicit substances. Trial registration: This review is registered on PROSPERO, ID number: CRD42018097203.