Background: Many people experience withdrawal symptoms when they attempt to stop antidepressants. Withdrawal symptoms are readily misconstrued for relapse or ongoing need for medication, contributing to long-term use (> 12 months). Long-term antidepressant use is increasing internationally yet is not recommended for most people. Long-term use is associated with adverse effects including weight gain, sexual dysfunction, lethargy, emotional numbing and increased risk of falls and fractures. This study aims to determine the effectiveness of two multi-strategy interventions (RELEASE and RELEASE+) in supporting the safe cessation of long-term antidepressants, estimate cost-effectiveness, and evaluate implementation strategies. Methods: Design: 3-arm pragmatic cluster randomised controlled trial effectiveness-implementation hybrid type-1. Setting: primary care general practices in southeast Queensland, Australia. Population: adults 18 years or older taking antidepressants for longer than 1 year. Practices will be randomised on a 1.5:1:1 ratio of Usual care:RELEASE:RELEASE+. Intervention: RELEASE for patients includes evidence-based information and resources and an invitation to medication review; RELEASE for GPs includes education, training and printable resources via practice management software. RELEASE+ includes additional internet support for patients and prescribing support including audit and feedback for GPs. Outcome measures: the primary outcome is antidepressant use at 12 months self-reported by patients. Cessation is defined as 0 mg antidepressant maintained for at least 2 weeks. Secondary outcomes: at 6 and 12 months are health-related quality of life, antidepressant side effects, well-being, withdrawal symptoms, emotional numbing, beliefs about antidepressants, depressive symptoms, and anxiety symptoms; and at 12 months 75% reduction in antidepressant dose; aggregated practice level antidepressant prescribing, and health service utilisation for costs. Sample size: 653 patients from 28 practices. A concurrent evaluation of implementation will be through mixed methods including interviews with up to 40 patients and primary care general practitioners, brief e-surveys, and study administrative data to assess implementation outcomes (adoption and fidelity). Discussion: The RELEASE study will develop new knowledge applicable internationally on the effectiveness, cost-effectiveness, and implementation of two multi-strategy interventions in supporting the safe cessation of long-term antidepressants to improve primary health care and outcomes for patients. Trial registration: ANZCTR, ACTRN12622001379707p. Registered on 27 October 2022.