BackgroundMental health problems are a crucial global public health concern. Owing to their cost-effectiveness and accessibility, conversational agent interventions (CAIs) are promising in the field of mental health care.ObjectiveThis study aims to present a thorough summary of the traits of CAIs available for a range of mental health problems, find evidence of efficacy, and analyze the statistically significant moderators of efficacy via a meta-analysis of randomized controlled trial.MethodsWeb-based databases (Embase, MEDLINE, PsycINFO, CINAHL, Web of Science, and Cochrane) were systematically searched dated from the establishment of the database to October 30, 2021, and updated to May 1, 2022. Randomized controlled trials comparing CAIs with any other type of control condition in improving depressive symptoms, generalized anxiety symptoms, specific anxiety symptoms, quality of life or well-being, general distress, stress, mental disorder symptoms, psychosomatic disease symptoms, and positive and negative affect were considered eligible. This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data were extracted by 2 independent reviewers, checked by a third reviewer, and pooled using both random effect models and fixed effects models. Hedgesgwas chosen as the effect size.ResultsOf the 6900 identified records, a total of 32 studies were included, involving 6089 participants. CAIs showed statistically significant short-term effects compared with control conditions in improving depressive symptoms (g=0.29, 95% CI 0.20-0.38), generalized anxiety symptoms (g=0.29, 95% CI 0.21-0.36), specific anxiety symptoms (g=0.47, 95% CI 0.07-0.86), quality of life or well-being (g=0.27, 95% CI 0.16-0.39), general distress (g=0.33, 95% CI 0.20-0.45), stress (g=0.24, 95% CI 0.08-0.41), mental disorder symptoms (g=0.36, 95% CI 0.17-0.54), psychosomatic disease symptoms (g=0.62, 95% CI 0.14-1.11), and negative affect (g=0.28, 95% CI 0.05-0.51). However, the long-term effects of CAIs for the most mental health outcomes were not statistically significant (g=−0.04 to 0.39). Personalization and empathic response were 2 critical facilitators of efficacy. The longer duration of interaction with conversational agents was associated with the larger pooled effect sizes.ConclusionsThe findings show that CAIs are research-proven interventions that ought to be implemented more widely in mental health care. CAIs are effective and easily acceptable for those with mental health problems. The clinical application of this novel digital technology will conserve human health resources and optimize the allocation of mental health services.Trial RegistrationPROSPERO CRD42022350130; https://tinyurl.com/mvhk6w9p