Background: Accelerated by technological advancements and the recent global pandemic, there is burgeoning interest in digital mental health literacy (DMHL) interventions that can positively affect mental health. However, existing work remains inconclusive regarding the effectiveness of DMHL interventions. Objective: This systematic review and meta-analysis investigated the components and modes of DMHL interventions, their moderating factors, and their long-term impacts on mental health literacy and mental health. Methods: We used a random-effects model to conduct meta-analyses and meta-regressions on moderating effects of DMHL interventions on mental health. Results: Using 144 interventions with 206 effect sizes, we found a moderate effect of DMHL interventions in enhancing distal mental health outcomes (standardized mean difference=0.42, 95% CI −0.10 to 0.73; P<.001) and a large effect in increasing proximal mental health literacy outcomes (standardized mean difference=0.65, 95% CI 0.59-0.74; P<.001). Uptake of DMHL interventions was comparable with that of control conditions, and uptake of DMHL interventions did not moderate the effects on both proximal mental health literacy outcomes and distal mental health outcomes. DMHL interventions were as effective as face-to-face interventions and did not differ by platform type or dosage. DMHL plus interventions (DMHL psychoeducation coupled with other active treatment) produced large effects in bolstering mental health, were more effective than DMHL only interventions (self-help DMHL psychoeducation), and were comparable with non-DMHL interventions (treatment as usual). DMHL interventions demonstrated positive effects on mental health that were sustained over follow-up assessments and were most effective in enhancing the mental health of emerging and older adults. Conclusions: For theory building, our review and meta-analysis found that DMHL interventions are as effective as face-to-face interventions. DMHL interventions confer optimal effects on mental health when DMHL psychoeducation is combined with informal, nonprofessional active treatment components such as skills training and peer support, which demonstrate comparable effectiveness with that of treatment as usual (client-professional interactions and therapies). These effects, which did not differ by platform type or dosage, were sustained over time. Additionally, most DMHL interventions are found in Western cultural contexts, especially in high-income countries (Global North) such as Australia, the United States, and the United Kingdom, and limited research is conducted in low-income countries in Asia and in South American and African countries. Most of the DMHL studies did not report information on the racial or ethnic makeup of the samples. Future work on DMHL interventions that target racial or ethnic minority groups, particularly the design, adoption, and evaluation of the effects of culturally adaptive DMHL interventions on uptake and mental health functioning, is needed. Such evidence can drive the adoption and implementation of DMHL interventions at scale, which represents a key foundation for practice-changing impact in the provision of mental health resources for individuals and the community. Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42023363995; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023363995
