Background <p>Youth (i.e., child and adolescent) mental health difficulties are a prevalent concern, with anxiety, depression, and disruptive behavior disorders being the most common presentations. Even though psychotherapy is often recommended to help youth and families manage mental health difficulties, recent meta-analyses suggest that youth psychotherapy is only moderately effective, highlighting a need for further improvement and innovation. Emotion dysregulation is a transdiagnostic risk factor across childhood emotional and behavioral disorders, yet despite the important connection between emotion regulation and psychopathology, little research has been conducted on emotion regulation as a potential mechanism of change during psychotherapy. This study will test the biobehavioral regulation of negative emotion as a transdiagnostic mechanism of change in youth psychotherapy using the Modular Approach to Therapy for Children with Anxiety, Depression, Trauma, or Conduct Problems (MATCH). MATCH is a well-researched therapy program for youth that is suitable for testing transdiagnostic mechanisms of treatment response.</p> Methods <p>This protocol describes a two-site randomized controlled trial that aims to recruit 202 youth between the ages of 8 to 15&#xa0;years with anxiety, depression, and/or disruptive behavior. Participants are randomized to the MATCH intervention condition or a waitlist control condition. Youth and their parent(s) in both conditions complete in-lab assessments and online questionnaires at the start of the study, every 3&#xa0;months (i.e., quarterly), and at post-test (i.e., following the intervention/waitlist period). Physiological measures of emotion regulation such as heart rate variability and skin conductance are acquired during lab-based tasks. Youth symptoms and emotion regulation are monitored weekly for both conditions. The primary outcome is change in youth symptoms of psychopathology at post-treatment, and whether this change is mediated by change in behavioral and physiological emotion regulation. Secondary outcomes include parental functioning, parenting, family functioning, impairment, and additional measures of youth psychopathology.</p> Discussion <p>Findings from the study are expected to enhance the understanding of processes that drive therapeutic change, ultimately leading to better therapy personalization and effectiveness.</p> Trial registration <p>ClinicalTrials.gov NCT05637320. Prospectively registered on November 15, 2022. <a href="https://clinicaltrials.gov/study/NCT05637320">https://clinicaltrials.gov/study/NCT05637320</a>.</p>