PurposeOff‐label medicines use is a common and sometimes necessary practice in many populations, with important clinical, ethical and financial consequences, including potential unintended harm or lack of effectiveness. No internationally recognized guidelines exist to aid decision‐makers in applying research evidence to inform off‐label medicines use. We aimed to critically evaluate current evidence informing decision‐making for off‐label use and to develop consensus recommendations to improve future practice and research.MethodsWe conducted a scoping review to summarize the literature on available off‐label use guidance, including types, extent and scientific rigor of evidence incorporated. Findings informed the development of consensus recommendations by an international multidisciplinary Expert Panel using a modified Delphi process. Our target audience includes clinicians, patients and caregivers, researchers, regulators, sponsors, health technology assessment bodies, payers and policy makers.ResultsWe found 31 published guidance documents on therapeutic decision‐making for off‐label use. Of 20 guidances with general recommendations, only 35% detailed the types and quality of evidence needed and the processes for its evaluation to reach sound, ethical decisions about appropriate use. There was no globally recognized guidance. To optimize future therapeutic decision‐making, we recommend: (1) seeking rigorous scientific evidence; (2) utilizing diverse expertise in evidence evaluation and synthesis; (3) using rigorous processes to formulate recommendations for appropriate use; (4) linking off‐label use with timely conduct of clinically meaningful research (including real‐world evidence) to address knowledge gaps quickly; and (5) fostering partnerships between clinical decision‐makers, researchers, regulators, policy makers, and sponsors to facilitate cohesive implementation and evaluation of these recommendations.ConclusionsWe provide comprehensive consensus recommendations to optimize therapeutic decision‐making for off‐label medicines use and concurrently drive clinically relevant research. Successful implementation requires appropriate funding and infrastructure support to engage necessary stakeholders and foster relevant partnerships, representing significant challenges that policy makers must urgently address.