Abstract Background A range of evidence informs healthcare decision-making, from formal research findings to ‘soft intelligence’ or local data, as well as practical experience or tacit knowledge. However, cultural and organisational factors often prevent the translation of such evidence into practice. Using a multi-level framework, this project will analyse how interactions between the evidence available and processes at the micro (individual/group) and meso (organisational/system) levels influence decisions to introduce or diffuse innovations in acute and primary care within the National Health Service in the UK. Methods/design This study will use a mixed methods design, combining qualitative and quantitative methods, and involves four interdependent work streams: (1) rapid evidence synthesis of relevant literature with stakeholder feedback; (2) in-depth case studies of ‘real-world’ decision-making in acute and primary care; (3) a national survey and discrete choice experiment; and (4) development of guidance for decision-makers and evaluators to support the use of evidence in decision-making. Discussion This study will enhance the understanding of decision-makers’ use of diverse forms of evidence. The findings will provide insights into how and why some evidence does inform decisions to introduce healthcare innovations, and why barriers persist in other cases. It will also quantify decision-makers’ preferences, including the ‘tipping point’ of evidence needed to shift stakeholders’ views. Practical guidance will be shared with healthcare decision-makers and evaluators on uses of evidence to enable the introduction and diffusion of innovation.