Objective eHealth is a useful tool to deliver lifestyle interventions for patients with cardiometabolic diseases. However, there are inconsistent findings about whether these eHealth interventions should be supported by a human professional, or whether self-help interventions are equally effective. Methods Databases were searched between January 1995 and October 2021 for randomized controlled trials on cardiometabolic diseases (cardiovascular disease, chronic kidney disease, type 1 and 2 diabetes mellitus) and eHealth lifestyle interventions. A multilevel meta-analysis was used to pool clinical and behavioral health outcomes. Moderator analyses assessed the effect of intervention type (self-help versus human-supported), dose of human support (minor versus major part of intervention), and delivery mode of human support (remote versus blended). One hundred seven articles fulfilled eligibility criteria and 102 unique (N = 20,781) studies were included. Results The analysis showed a positive effect of eHealth lifestyle interventions on clinical and behavioral health outcomes (p <.001). However, these effects were not moderated by intervention type (p =.169), dose (p =.698), or delivery mode of human support (p =.557). Conclusions This shows that self-help eHealth interventions are equally effective as human-supported ones in improving health outcomes among patients with cardiometabolic disease. Future studies could investigate whether higher-quality eHealth interventions compensate for a lack of human support. Meta-analysis registration: PROSPERO CRD42021269263.