Transphobia and stigma remain barriers to seeking mental health care for gender-diverse adolescents. To examine the utility of brief social contact-based video interventions of transgender protagonists with depression to reduce transphobia and depression-related stigma and increase treatment-seeking intentions among adolescents in the general population. During August 2021, a total of 1437 participants were recruited and randomly assigned to 1 of 4 video-based conditions in a 2:2:1:1 ratio: (1) transgender adolescent girls, (2) transgender adolescent boys, (3) cisgender adolescent girls, or (4) cisgender adolescent boys. In each of the approximately 110-second videos, an empowered presenter shared their personal story about coping with depression and reaching out for help. The primary outcome was the score on the Attitudes Toward Transgender Men and Women (ATTMW) scale. Secondary outcomes were (1) a "gender thermometer" rating for warmth in transgender perception, (2) the Depression Stigma Scale (DSS) score, and (3) the General Health-Seeking Questionnaire (GHSQ) score. Of the 1437 randomized participants, 1098 (76%) completed the postintervention assessment and passed all the validity tests (mean [SD] age, 16.9 [1.2] years; 481 [44%] male; 640 [58%] White). A significant change in attitudes toward transgender youth was found within the intervention group only (mean [SD] ATTMW scores: intervention group, 34.6 [23.1] at baseline to 32.8 [24.2] after intervention; P < .001; control group, 33.5 [23.4] at baseline to 32.4 [24.1] after intervention; P = .01). The mean (SD) total DSS scores decreased significantly across study groups (intervention: 1.3 [3.3]; control: 1.7 [3.3]; P < .001). A significant increase in intention to seek help from a parent was found in the intervention (mean [SD] GHSQ score, 0.2 [1.1]) and control (mean [SD] GHSQ score, 0.3 [1.2]) groups (P < .001), as was a decrease in those not wanting to seek help from anyone (mean [SD] GHSQ score: intervention, 0.2 [1.6], P = .009; control, 0.3 [1.2], P < .001) Secondary analyses revealed significant differences in baseline ATTMW scores and intervention effects between transgender and gender-diverse and cisgender participants and between lesbian, gay, bisexual, or queer (LGBQ) and straight participants (F = 36.7, P < .001) and heterosexual participants (F = 37.0, P < .001). A significant difference was also found in mean (SD) transgender warmth scores from baseline to after intervention between groups (2.6° [13.1°] in the intervention group vs 0.4° [8.3°] in the control group; P < .001). In this randomized clinical trial, brief social contact-based videos proved efficacious in reducing transphobia and depression-related stigma and in increasing treatment-seeking intentions among adolescents in the general population. By personifying, individualizing, and providing face and voice to the experience of transgender youth, other adolescents, especially those who are cisgender and/or of a heterosexual orientation, can gain empathetic insights into the lives of their often marginalized and stigmatized fellow youth. ClinicalTrials.gov Identifier: NCT04969003.