Objectives and ambition: Substance use disorder (SUD) is associated with a high global burden of disease, with 5.4% of all disability-adjusted life years lost due to alcohol and illicit drugs. Highly prevalent multimorbidity includes polysubstance use, mental health conditions, and other non-communicable and infectious diseases. Where traditional treatments are insufficient alone, music therapy (MT) is highly engaging and improves motivation and craving, but its long-term effects are unknown. Methodology: In a diverse group of people with SUD across a wide range of age, gender, socioeconomic, and cultural background, a parallel 3-arm assessor-blinded pragmatic multinational randomised clinical trial with embedded exploratory trials and mechanistic studies will determine long-term effects of active music groups (AMG) and music listening groups (MLG) versus treatment as usual (TAU) on addiction severity (primary: 1 year), recovery, and other health and socioeconomic outcomes. Embedded trials will examine short-term effects of individual components of TAU combined with AMG or MLG to determine the best combinations of interventions. Experimental studies will examine mechanisms using neuropsychological tests and brain imaging. With 600 participants in 7 countries randomised, the trial has 80% power on the primary outcome. Patient representatives, HTA bodies, and interventionists have been involved from conception and will ensure feasibility and applicability across Europe. Impact: FALCO will reduce disease burden through innovative, effective, and affordable treatment and will strengthen research and innovation expertise. Recommendations from FALCO will inform intervention delivery across Europe and beyond, leading to increased safety, effectiveness and cost-effectiveness, and improved quality of life for people with SUD. Stakeholders will be involved in communicating findings in all European countries and regions and ensuring that findings are effectively implemented.