Background Multiple sclerosis (MS) is one of the world’s most common neurologic disorders leading to severe disability in young adults. MS-related fatigue directly impacts on the quality of life and activity levels of people with MS. Self-management strategies are used to support them in the care of their health. Mobile health (mHealth) solutions can offer tools to help symptom management. Following a user-centered design and evidence-based process, an mHealth solution called More Stamina was created to help persons with MS manage their fatigue. Objective The overall study aims are to explore the feasibility, acceptability, and usability of More Stamina, a mobile app for fatigue self-management for persons with MS. Methods A mixed-methods, multicenter study will be used to assess the feasibility, acceptability, and usability of More Stamina. The study will take place during the third and fourth quarters of 2020 (Q3-Q4 2020) in 3 locations: Argentina, Spain, and Switzerland. A longitudinal cohort study will take place, and think-aloud protocols, open-ended interviews, and short answer questionnaires will be used. Persons with MS will be recruited from the different locations. This study seeks to enroll at least 20 patients that meet the criteria from each site for the longitudinal cohort study (total n=60). Results Ethical approval has been granted in Argentina and is pending in Spain and Switzerland. Outcomes will be published in peer-reviewed medical journals and presented at international conferences. Conclusions Findings from this study will be used to help understand the role that mHealth can play in fatigue management in MS. Trial Registration ClinicalTrials.gov NCT04244214; https://clinicaltrials.gov/ct2/show/NCT04244214 International Registered Report Identifier (IRRID) PRR1-10.2196/18196