IMPORTANCEAdolescent major depressive disorder (MDD) prevalence has nearly doubled in the past decade. The US Preventive Services Task Force endorses universal adolescent MDD screening in primary care; however, most adolescents lack preventive health care, resulting in worsening disparities in MDD screening and treatment. OBJECTIVE To evaluate the effectiveness of universal adolescent MDD screening in the school setting in an effort to reduce disparities and improve MDD identification and treatment initiation. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial, conducted from November 6, 2018, to November 20, 2020, compared the usual school practice of targeted or selected screening based on observable behaviors of concern with universal MDD screening. Students within an identified school were randomized by grade to 1 of the 2 study groups. Study groups were compared using mixed-effects logistic regression. Participants included students in grades 9 through 12 enrolled at 1 of the 14 participating Pennsylvania public high schools.Author affiliations and article information are listed at the end of this article.