Background: Around one-third of workdays lost in Norway are due to musculoskeletal conditions, with persistent (chronic) pain being the most frequent cause of sick leave and work disability. Increasing work participation for people with persistent pain improves their health, quality of life, and well-being and reduces poverty; however, it is not clear how to best help unemployed people who have persistent pain to return to work. The aim of this study is to examine if a matched work placement intervention featuring case manager support and work-focused healthcare improves return to work rates and quality of life for unemployed people in Norway with persistent pain who want to work. Methods: We will use a cohort randomised controlled approach to test the effectiveness and cost-effectiveness of a matched work placement intervention featuring case manager support and work-focused healthcare compared to those receiving usual care in the cohort alone. We will recruit people aged 18–64, who have been out of work for at least 1 month, had pain for more than 3 months, and want to work. Initially, all (n = 228) will be recruited to an observational cohort study on the impact of being unemployed with persistent pain. We will then randomly select one in three to be offered the intervention. The primary outcome of sustained return to work will be measured using registry and self-reported data, while secondary outcomes include self-reported levels of health-related quality of life and physical and mental health. Outcomes will be measured at baseline and 3, 6, and 12 months post-randomisation. We will run a process evaluation parallel to the intervention exploring implementation, continuity of the intervention, reasons for participating, declining participation, and mechanisms behind cases of sustained return to work. An economic evaluation of the trial process will also be conducted. Discussion: The ReISE intervention is designed to increase work participation for people with persistent pain. The intervention has the potential to improve work ability by collaboratively navigating obstacles to working. If successful, the intervention may be a viable option for helping people in this population. Trial registration: ISRCTN Registry 85,437,524 Registered on 30 March 2022.