BackgroundSocial media has emerged as an effective tool to mitigate preventable and costly health issues with social network interventions (SNIs), but a precision public health approach is still lacking to improve health equity and account for population disparities.ObjectiveThis study aimed to (1) develop an SNI framework for precision public health using control systems engineering to improve the delivery of digital educational interventions for health behavior change and (2) validate the SNI framework to increase organ donation awareness in California, taking into account underlying population disparities.MethodsThis study developed and tested an SNI framework that uses publicly available data at the ZIP Code Tabulation Area (ZCTA) level to uncover demographic environments using clustering analysis, which is then used to guide digital health interventions using the Meta business platform. The SNI delivered 5 tailored organ donation–related educational contents through Facebook to 4 distinct demographic environments uncovered in California with and without an Adaptive Content Tuning (ACT) mechanism, a novel application of the Proportional Integral Derivative (PID) method, in a cluster randomized trial (CRT) over a 3-month period. The daily number of impressions (ie, exposure to educational content) and clicks (ie, engagement) were measured as a surrogate marker of awareness. A stratified analysis per demographic environment was conducted.ResultsFour main clusters with distinctive sociodemographic characteristics were identified for the state of California. The ACT mechanism significantly increased the overall click rate per 1000 impressions (β=.2187;P<.001), with the highest effect on cluster 1 (β=.3683;P<.001) and the lowest effect on cluster 4 (β=.0936;P=.053). Cluster 1 is mainly composed of a population that is more likely to be rural, White, and have a higher rate of Medicare beneficiaries, while cluster 4 is more likely to be urban, Hispanic, and African American, with a high employment rate without high income and a higher proportion of Medicaid beneficiaries.ConclusionsThe proposed SNI framework, with its ACT mechanism, learns and delivers, in real time, for each distinct subpopulation, the most tailored educational content and establishes a new standard for precision public health to design novel health interventions with the use of social media, automation, and machine learning in a form that is efficient and equitable.Trial RegistrationClinicalTrials.gov NTC04850287; https://clinicaltrials.gov/ct2/show/NCT04850287