This trial introduces a novel transdiagnostic intervention (Shaping Healthy Minds) designed to address the gap in effective interventions for people with complex and comorbid presentations including anxiety, disturbed mood, and trauma sequelae. Shaping Healthy Minds is a modular intervention which synthesises several evidence-based treatment techniques, allowing for standardised, yet flexible, treatment delivery. We conducted a patient-level two-arm randomised controlled trial (HARMONIC) that compared Shaping Healthy Minds to psychological treatment-as-usual (PTAU) for individuals aged >18 years (n = 42). Participants met criteria for at least two comorbid mood, anxiety, obsessive-compulsive or trauma/stressor disorder diagnoses and were recruited from outpatient psychological services within the UK National Health Service (NHS). This early phase trial aimed to estimate the efficacy, feasibility, and acceptability of the transdiagnostic intervention. We obtained estimates of likely effect size and acquired basic demographic, cognitive and behavioural data to assess potential mediators and moderators of outcome in preparation for a later phase fully-powered efficacy trial. Co-primary outcomes were self-reported depression and anxiety symptoms, disability and functional impairment; and the trial provided point estimates of efficacy for Shaping Healthy Minds versus Psychological TAU with moderate effect sizes in favour of Shaping Healthy Minds at post-treatment (Cohen’s d estimates ranging from 0.60-0.92) and at 3-month follow-up (Cohen’s d 0.41-0.48). Secondary outcomes included number of diagnoses and changes in transdiagnostic processes. The project has demonstrated that a full trial is feasible, and that the Shaping Healthy Minds treatment approach appears likely to be efficacious compared to PTAU. The trial procedures were approved by the Health Research Authority of the NHS of the UK (East of England, Reference: 16/EE/0095). The results of this feasibility trial will inform future large-scale trials of psychological interventions for co-occurring mood, anxiety, and stressor-related disorders.Trial registration NCT03143634.