It is widely acknowledged that vaccine hesitancy is a multifaceted problem that cannot be addressed by a single strategy. Behavior change theories and social media tools may together help to guide the design of interventions aimed at improving vaccination uptake. This systematic review aims to identify the breadth and effectiveness of such theories and tools. The systematic review search was performed in PubMed, Scopus, ACM, Cochrane Library, ProQuest, and Web of Science databases for studies between January 2011 and January 2021 that applied social media tools to increase vaccine confidence or improve vaccination uptake. The literature search yielded a total of 3,065 publications. Twenty articles met the eligibility criteria, 12 of which were theory-based interventions. The result shows that the Health Belief Model was the most frequently deployed theory, and the most common social media tool was educational posts, followed by dialogue-based groups, interactive websites, and personal reminders. Theory-based interventions were generally more measurable and comparable and had more evidence to trigger the positive behavior change. Fifteen studies reported the effectiveness in knowledge gain, intention increase, or behavior change. Educational messages were proved to be effective in increasing knowledge but less helpful in triggering behavior change. Dialogue-based social media intervention performed well in improving people’s intention to vaccinate. Interventions informed by behavior change theory and delivered via social media platforms offer an important opportunity for addressing vaccine hesitancy. This review highlights the need to use a multitheory framework and tailoring social media interventions to the specific circumstances and needs of the target audience in future interventions. The results and insights gained from this review will be of assistance to future studies.