Background: Stigma toward people with mental illness presents serious consequences for the impacted individuals, such as social exclusion and increased difficulties in the recovery process. Recently, several interventions have been developed to mitigate public stigma, based on the use of innovative technologies, such as virtual reality and video games. Objective: This review aims to systematically review, synthesize, measure, and critically discuss experimental studies that measure the effect of technological interventions on stigmatization levels. Methods: This systematic review and meta-analysis was based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines and included studies in English and Spanish published between 2016 and 2021. Searches were run in 5 different databases (ie, PubMed, PsycInfo, Scopus, Cochrane Library, and ScienceDirect). Only randomized controlled trials were included. Two independent reviewers determined the eligibility, extracted data, and rated methodological quality of the studies. Meta-analyses were performed using the Comprehensive Meta-Analysis software. Results: Based on the 1158 articles screened, 72 articles were evaluated as full text, of which 9 were included in the qualitative and quantitative syntheses. A diversity of interventions was observed, including video games, audiovisual simulation of hallucinations, virtual reality, and electronic contact with mental health services users. The meta-analysis (n=1832 participants) demonstrated that these interventions had a consistent medium effect on reducing the level of public stigma (d=-0.64; 95% CI 0.31-0.96; P<.001). Conclusions: Innovative interventions involving the use of technologies are an effective tool in stigma reduction, therefore new challenges are proposed and discussed for the demonstration of their adaptability to different contexts and countries, thus leading to their massification. Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42021261935; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021261935 (JMIR Serious Games 2022;10(2):e35099) doi: 10.2196/35099