Background: Children and young people with epilepsy are significantly more likely to experience multiple mental health problems, including anxiety, depression and behavioural difficulties, compared to youth without chronic physical health needs. Yet the majority of mental health problems go undetected and untreated in this population and can seriously impact social, occupational and educational functioning into adulthood. Currently, mental and physical health care is not integrated in paediatric epilepsy. Existing evidence-based psychological interventions typically target only one problem area and do not meet the specific needs of young people with epilepsy. Objectives: The aim of this research programme was to transform the treatment of mental health disorders in young people with epilepsy. Our objectives were to: 1. adapt and personalise an existing modular cognitive–behavioural treatment for multiple mental health disorders to address the particular needs of young people with epilepsy; 2. integrate the intervention into paediatric epilepsy services; 3. evaluate the clinical and cost-effectiveness of the intervention; and 4. understand the experience of the intervention from the perspectives of patients and families. Design and methods: Four complementary work packages linked to our objectives comprised: (1) multimethod improvement science work to develop the Mental Health Intervention for Children with Epilepsy treatment, (2) training and supervising staff working with young people with epilepsy to deliver the treatment with competence and fidelity, (3) a multicentre randomised controlled trial to compare the clinical and cost-effectiveness of the treatment in addition to assessment-enhanced usual care with assessment-enhanced usual care alone and (4) longitudinal qualitative study of young people and their families to explore patient experience. Setting: The programme took place in National Health Service paediatric epilepsy services across England and Northern Ireland. Participants: Participants were aged 3–18 years with epilepsy and at least one common mental health disorder. Many participants had multiple mental health problems, were neurodivergent and/or had intellectual disabilities. Interventions: Participants in the active treatment arm of the trial received up to 20 weekly sessions of the personalised treatment, which was delivered remotely by professionals with limited prior experience in mental health. Main outcome measures: Our primary outcome measure in the randomised controlled trial was the Strengths and Difficulties Questionnaire, a parent-reported standardised measure of severity of youth mental health symptoms at 6 months post randomisation. Secondary outcome measures included impact scales of mental health symptoms, health-related quality of life and parental mental health. Results: Using improvement science methods, we personalised an existing modular psychological intervention. We coproduced a core module addressing epilepsy-specific issues in mental health, and three optional modules to target stigma, parental mental health and the transition to adulthood. We trained staff from paediatric epilepsy settings to deliver the intervention with competence and fidelity over 6 months. We conducted the first randomised controlled trial of a modular mental health treatment for young people with epilepsy, with excellent rates of retention and follow-up. Participants in the Mental Health Intervention for Children with Epilepsy group reported a significantly greater reduction in emotional and behavioural symptoms at 6 months post randomisation compared to the assessment-enhanced usual care control group (Cohen's d = 0.3). These gains were maintained at 12 months' follow-up (Cohen's d = 0.4). Parental mental health also significantly improved in the treatment group, compared to a deterioration in the control group. The average cost of the Mental Health Intervention for Children with Epilepsy (including delivery, supervision and training) was approximately £1466 per participant, and when youth and parent quality-adjusted life-years were combined, the Mental Health Intervention for Children with Epilepsy treatment was cost-effective at the National Institute for Health and Care Excellence-preferred threshold for cost per quality-adjusted life-year (incremental cost per quality-adjusted life-year for Mental Health Intervention for Children with Epilepsy vs. control = £6311). Longitudinal qualitative interviews highlighted positive changes in feelings and behaviours of participants following therapy, independent of the child's age, gender or level of learning needs. Limitations: Limitations of our work include the lack of an active treatment control group in the randomised controlled trial, reliance on parent-reported outcome measures due to challenges in the availability and suitability of youth-report measures in this population, limitations in measurement of health-related quality of life for young people impacting on economic analyses, and a lack of power to explore the effects of therapist competence on outcome. Conclusions: The multiple mental health needs of young people with epilepsy can be identified and successfully treated from within existing paediatric epilepsy services, with a personalised modular cognitive–behavioural treatment. This model of integrated health care has implications for other chronic physical health conditions.