BACKGROUND: Digital technology is an opportunity for public health interventions to reach a large part of the population. OBJECTIVE: This systematic literature review aimed to assess the effectiveness of mobile health-based interventions in reducing the risk of cardiovascular disease and type 2 diabetes mellitus. METHODS: We conducted the systematic search in 7 electronic databases using a predefined search strategy. We included articles published between inception of the databases and March 2019 if they reported on the effectiveness of an intervention for prevention of cardiovascular disease or type 2 diabetes via mobile technology. One researcher performed the search, study selection, data extraction, and methodological quality assessment. The steps were validated by the other members of the research team. RESULTS: The search yielded 941 articles for cardiovascular disease, of which 3 met the inclusion criteria, and 732 for type 2 diabetes, of which 6 met the inclusion criteria. The methodological quality of the studies was low, with the main issue being nonblinding of participants. Of the selected studies, 4 used SMS text messaging, 1 used WhatsApp, and the remaining ones used specific smartphone apps. Weight loss and reduction in BMI were the most reported successful outcomes (reported in 4 studies). CONCLUSIONS: Evidence on the effectiveness of mobile health-based interventions in reducing the risk for cardiovascular disease and type 2 diabetes is low due to the quality of the studies and the small effects that were measured. This highlights the need for further high-quality research to investigate the potential of mobile health interventions. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) CRD42019135405; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=135405.