Background Social media platforms are frequently used in health communication campaigns. Common understandings of campaign effects posit a sequential and linear series of steps from exposure to behavior change, commonly known as the hierarchy of effects model (HOE). These concepts need to be reevaluated in the age of social media, which are interactional and communal. Objective This review aims to update the traditional HOE for health communication campaigns in the context of social media, including identifying indicators of effectiveness and how these are conceptualized to lead to health-related outcomes. Methods We conducted a systematic review of studies following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines reporting on the use of social media as part of health communication campaigns, extracting campaign information such as objectives, platforms used, and measures of campaign performance. We used these data, combined with our understanding of the HOE, to develop an updated conceptual model of social media campaign effects. Results We identified 99 eligible studies reporting on 93 campaigns, published between 2012 and 2022. The campaigns were conducted in over 20 countries, but nearly half (n=42) were conducted in the United States. Campaigns targeted a variety of health issues and predominantly used Facebook, Twitter, Instagram, and YouTube. Most campaigns (n=81) set objectives targeting awareness or individual behavior change. Process measures (n=68; eg, reach and impressions) and engagement measures (n=73; eg, likes and retweets) were reported most frequently, while two-fifths (n=42) did not report any outcomes beyond engagement, such as changes in knowledge, behavior, or social norms. Most campaigns (n=55) collected measures that did not allow them to determine if the campaign objective had been met; that is, they were process evaluations only. Based on our review, our updated model suggests that campaign exposure can lead to individual behavior change and improved health outcomes, either through a direct or indirect pathway. Indirect pathways include exposure through social and policy changes. “Engagement” is positioned as critical to success, replacing awareness in the traditional HOE, and all types of engagement are treated as equal and good. No consideration is being given to potential negative engagement, such as the distribution of misinformation. Additionally, the process is no longer linear and sequential, with circular pathways evident, such as engagement not only influencing behavior change but also generating additional exposure to campaign messages. Conclusions Our review has highlighted a change in conventional understandings of how campaigns can influence health outcomes in the age of social media. The updated model we propose provides social media campaigners with a starting point to develop and tailor campaign messages and allows evaluators to identify critical assumptions to test, including the role and value of “engagement.” Trial Registration PROSPERO CRD42021287257; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=287257