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BACKGROUND Chronic pain conditions implicate numerous physical and psychological challenges, and while psychosocial self-management interventions can be of benefit for people living with chronic pain, such in-person treatment is not always accessible. Digital self-management approaches could improve this disparity, potentially bolstering outreach and providing easy, relatively low-cost access to pain self-management interventions. OBJECTIVE The current randomized controlled trial aimed to evaluate the short-term efficacy of EPIO, a digital self-management intervention for people living with chronic pain. METHODS Patients (N=266) were randomly assigned to the EPIO intervention (n=132) or a care-as-usual control group (n=134). Outcome measures included pain interference (BPI; primary outcome measure), anxiety and depression (HADS), self-regulatory fatigue (SRF-18), health-related quality of life (SF-36/RAND-36), pain catastrophizing (PCS), and pain acceptance (CPAQ). Linear regression models employed change scores as dependent variables. RESULTS Participants were primarily women (81%), median age of 49 (range 22-78), with a variety of pain conditions. Analyses (n=229) after 3 months revealed no statistical significance for the primary outcome of pain interference, but significant reductions in the secondary outcomes of depression (mean difference (MD) -.90, P=.034) and self-regulatory fatigue (MD -2.76, P=.008) in favor of the intervention group. No other statistically significant changes were observed at 3 months. Participants described EPIO as useful (ie, totally agree or agree; 95/109, 87%) and easy to use (101/109, 93%), with easily understandable exercises (106/109, 97%). CONCLUSIONS Evidence-informed, user-centered digital pain self-management interventions such as EPIO may have the potential to effectively support self-management and improve psychological functioning in the form of reduced symptoms of depression and improved capacity to regulate thoughts, feelings, and behavior for people living with chronic pain. CLINICALTRIAL ClinicalTrials.gov NCT03705104; https://clinicaltrials.gov/ct2/show/NCT03705104 INTERNATIONAL REGISTERED REPORT RR2-10.2196/23893