Vaccination programs are instrumental in prolonging and improving people's lives by preventing diseases such as measles, diphtheria, tetanus, pertussis, and influenza from escalating into fatal epidemics. Despite the significant impact of these programs, a substantial number of individuals, including 20 million infants annually, lack sufficient access to vaccines. Therefore, it is imperative to raise awareness about vaccination programs. This study aims to investigate the potential utilization of social media, assessing its scalability and robustness in delivering accurate and reliable information to individuals who are contemplating vaccination decisions for themselves or on behalf of their children. The protocol for this review is registered in PROSPERO (identifier CRD42022304229) and is being carried out in compliance with the Cochrane Handbook for Systematic Reviews of Interventions. Comprehensive searches have been conducted in databases including MEDLINE, Embase, PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health), CENTRAL (Cochrane Central Register of Controlled Trials), and Google Scholar. Only randomized controlled trials (RCTs) were deemed eligible for inclusion in this study. The target population encompasses the general public, including adults, children, and adolescents. The defined interventions comprise platforms facilitating 2-way communication for sharing information. These interventions were compared against traditional interventions and teaching methods, referred to as the control group. The outcomes assessed in the included studies encompassed days unvaccinated, vaccine acceptance, and the uptake of vaccines compared with baseline. The studies underwent a risk-of-bias assessment utilizing the Cochrane Risk-of-Bias tool for RCTs, and the certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) assessment. This review included 10 studies, detailed in 12 articles published between 2012 and 2022, conducted in the United States, China, Jordan, Australia, and Israel. The studies involved platforms such as Facebook, Twitter, WhatsApp, and non-general-purpose social media. The outcomes examined in these studies focused on the uptake of vaccines compared with baseline, vaccine acceptance, and the number of days individuals remained unvaccinated. The overall sample size for this review was 26,286, with individual studies ranging from 58 to 21,592 participants. The effect direction plot derived from articles of good and fair quality indicated a nonsignificant outcome (P=.12). The findings suggest that, in a real-world scenario, an equal number of positive and negative results may be expected due to the interventions' impact on the acceptance and uptake of vaccines. Nevertheless, there is a rationale for accumulating experience to optimize the use of social media with the aim of enhancing vaccination rates. Social media can serve as a tool with the potential to disseminate information and boost vaccination rates within a population. However, relying solely on social media is not sufficient, given the complex structures at play in vaccine acceptance. Effectiveness hinges on various factors working in tandem. It is crucial that authorized personnel closely monitor and moderate discussions on social media to ensure responsible and accurate information dissemination.