Background A total of 2.8 million people are living with multiple sclerosis and due to disparities in access to medicines, the ability to treat this condition varies widely. Off-label disease-modifying therapies are sometimes more available or affordable in different health systems. Appropriate methodology is integral in creating high-quality and trustworthy guidelines. In this article, we outline Multiple Sclerosis International Federation’s (MSIF) approach to creating guidelines for off-label treatments for multiple sclerosis. Methods We use the Guidelines International Network (GIN)-McMaster Guideline Development Checklist and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Evidence-to-Decision (EtD) framework. We developed detailed health descriptors for health outcomes and the panel drafted PICO (Population, Intervention, Comparator, Outcome) questions and prioritised outcomes. We collaborate with independent organisations, which systematically review and collate the information. We are actively engaging stakeholders and consulting with relevant organisations, boards, working groups and individuals. Results The draft guideline recommendations will be published for open comment and stakeholders will be encouraged to endorse and disseminate the guidelines. Our methodology ensures integrity and transparency in the criteria, evidence and judgement used to make recommendations. Conclusions This approach will facilitate transparent creation of high-quality and trustworthy guidelines, and allow the global guidelines to be adopted or adapted into national settings.