Background: Numerous studies have demonstrated the effectiveness of digital interventions for improving the mental health of university students. However, low rates of engagement with these interventions are an ongoing challenge and can compromise effectiveness. Brief, transdiagnostic, web-based video interventions are capable of targeting key mental health and related issues affecting university students and may be more engaging and accessible for this population., Objective: This study used a 2-arm randomized controlled trial to evaluate the effectiveness of Uni Virtual Clinic-Lite (UVC-Lite), a fully automated, transdiagnostic, web-based video intervention, relative to an attention-control condition. The primary outcomes were symptoms of depression and generalized anxiety disorder. The secondary outcomes included psychological distress, social anxiety symptoms, body appreciation, quality of life, well-being, functioning, general self-efficacy, academic self-efficacy, and help seeking. Program use (intervention uptake and engagement) and satisfaction were also assessed., Methods: University students (n=487) with mild to moderate symptoms of distress were recruited from universities across Australia and randomly allocated to receive access to the UVC-Lite intervention or an attention-control condition targeting general health for a period of 6 weeks. UVC-Lite includes 12 modules, each comprising a brief animated video and an accompanying exercise. Of the 12 modules, 7 also included a brief symptom screening quiz. Outcomes were assessed at baseline, postintervention, and 3- and 6-months postintervention., Results: The primary and secondary outcomes were analyzed on an intention-to-treat basis using mixed models repeated measures ANOVA. The intervention was not found to be effective relative to the control condition on any of the primary or secondary outcomes. While 67.9% (114/168) of participants accessed at least 1 module of the intervention, module completion was extremely low. Subgroup analyses among those who engaged with the program (completed at least 1 video) and those with higher baseline distress (Distress Questionnaire-5 score ≥15) did not reveal any differences between the conditions over time. However, uptake (accessing at least 1 video) and engagement (completing at least 1 video) were higher among those with higher baseline symptoms. Satisfaction with the intervention was high., Conclusions: The UVC-Lite intervention was not effective relative to a control program, although it was associated with high satisfaction among students and was not associated with symptom deterioration. Given the challenges faced by universities in meeting demand for mental health services, flexible and accessible interventions such as UVC-Lite have the potential to assist students to manage symptoms of mental health problems. However, low uptake and engagement (particularly among students with lower levels of symptomatology) are significant challenges that require further attention. Future studies should examine the effectiveness of the intervention in a more highly symptomatic sample, as well as implementation pathways to optimize effective engagement with the intervention., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12621000375853; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380146., (©Louise M Farrer, Hayley M Jackson, Amelia Gulliver, Alison L Calear, Liana Leach, Penelope Hasking, Natasha Katruss, Philip J Batterham. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 13.08.2024.)