Background Meditation apps have surged in popularity in recent years, with an increasing number of individuals turning to these apps to cope with stress, including during the COVID-19 pandemic. Meditation apps are the most commonly used mental health apps for depression and anxiety. However, little is known about who is well suited to these apps. Objective This study aimed to develop and test a data-driven algorithm to predict which individuals are most likely to benefit from app-based meditation training. Methods Using randomized controlled trial data comparing a 4-week meditation app (Healthy Minds Program [HMP]) with an assessment-only control condition in school system employees (n=662), we developed an algorithm to predict who is most likely to benefit from HMP. Baseline clinical and demographic characteristics were submitted to a machine learning model to develop a “Personalized Advantage Index” (PAI) reflecting an individual’s expected reduction in distress (primary outcome) from HMP versus control. Results A significant group × PAI interaction emerged (t658=3.30; P=.001), indicating that PAI scores moderated group differences in outcomes. A regression model that included repetitive negative thinking as the sole baseline predictor performed comparably well. Finally, we demonstrate the translation of a predictive model into personalized recommendations of expected benefit. Conclusions Overall, the results revealed the potential of a data-driven algorithm to inform which individuals are most likely to benefit from a meditation app. Such an algorithm could be used to objectively communicate expected benefits to individuals, allowing them to make more informed decisions about whether a meditation app is appropriate for them. Trial Registration ClinicalTrials.gov NCT04426318; https://clinicaltrials.gov/ct2/show/NCT04426318