We describe initial pilot findings from a novel school-based approach to reduce youth depression and suicidality, the Empowering a Multimodal Pathway Towards Healthy Youth (EMPATHY) program. Here we present the findings from the pilot cohort of 3,244 youth aged 11–18 (Grades 6-12). They were screened for depression, suicidality, anxiety, use of drugs, alcohol, or tobacco (DAT), quality-of-life, and self-esteem. Additionally, all students in Grades 7 and 8 (mean ages 12.3 and 13.3 respectively) also received an 8-session cognitive-behavioural therapy (CBT) based program designed to increase resiliency to depression. Following screening there were rapid interventions for the 125 students (3.9%) who were identified as being actively suicidal, as well as for another 378 students (11.7%) who were felt to be at higher-risk of self-harm based on a combination of scores from all the scales. The intervention consisted of an interview with the student and their family followed by offering a guided internet-based CBT program. Results from the 2,790 students who completed scales at both baseline and 12-week follow-up showed significant decreases in depression and suicidality. Importantly, there was a marked decrease in the number of students who were actively suicidal (from n=125 at baseline to n=30 at 12-weeks). Of the 503 students offered the CBT program 163 (32%) took part, and this group had significantly lower depression scores compared to those who didn’t take part. There were no improvements in self-esteem, quality-of-life, or the number of students using DAT. Only 60 students (2% of total screened) required external referral during the 24-weeks following study initiation. These results suggest that a multimodal school-based program may provide an effective and pragmatic approach to help reduce youth depression and suicidality. Further research is required to determine longer-term efficacy, reproducibility, and key program elements.Trial RegistrationClinicalTrials.gov NCT02169960