Brief, scalable, and transdiagnostic prevention efforts are needed to prevent depression and anxiety among college students. Growth mindset interventions are brief, often web-based interventions to prevent or reduce depression symptom severity that have not yet been evaluated within a college student population. In this study, college students (n = 371) were randomized to either a web-based growth mindset intervention or a psychoeducation control. We examined acceptability and usability ratings as well as the impact of the intervention on new-onset depression and anxiety and symptom trajectories as assessed by the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) over a six-month period. Results indicated that participants found the intervention to be acceptable and usable. Assessing the potential of the intervention as a universal prevention approach among participants below clinical cutoffs at baseline (GAD-7 or PHQ-9 <10, N = 239 and N=229, respectively), the intervention was not associated with a reduction in new-onset depression or anxiety, nor a reduction in depression symptom trajectories compared with the control group. Control group participants experienced a greater increase in anxiety symptoms severity than participants receiving the intervention (d = 0.24). Among individuals above clinical cutoffs at baseline (GAD-7 ≥ 10; N=132, or PHQ-9 ≥ 10; N=142), the intervention reduced symptom severity to the extent that it changed beliefs about emotions. While the intervention was acceptable among college students and demonstrated promising effects on anxiety symptom severity and changes in beliefs about emotions, more work is needed to strengthen this approach to prevent new-onset depression and anxiety.Trial registration: ClinicalTrials.gov Identifier: NCT03707522