BACKGROUND: The widespread implementation of interventions is often hindered by a decline and variability in effectiveness across implementation sites. It is anticipated that variations in the characteristics of the external context in different sites, such as the political and funding environment, socio-cultural context, physical environment or population demographics can influence implementation outcome. However, there is only a limited understanding about which and how external contextual factors influence implementation. We aim to develop a comprehensive framework conceptualising the influence of external contextual factors on implementation, particularly when spreading health and social care interventions within or across countries. METHODS: The review will use the 'best fit' framework synthesis approach. In the first stage of the review, we will examine existing frameworks, models, concepts and theories on external contextual factors and their influence on implementation from a variety of sectors and disciplines including health and social care, education, environmental studies and international development fields. The resulting a priori meta-framework will be tested and refined in the second review stage by analysing evidence from empirical studies focusing on the implementation of health and social care interventions within or across countries. Searches will be conducted in bibliographic databases such as MEDLINE, ERIC, HMIC and IBSS, grey literature sources and on relevant websites. We will also search reference lists, relevant journals, perform citation searches and ask experts in the field. There is no restriction to study type, setting, intervention type or implementation strategy to enable obtaining a broad and in-depth knowledge from various sources of evidence. DISCUSSION: The review will lead to a comprehensive framework for understanding the influence of external contextual factors on implementation, particularly when spreading health and social care interventions within or across countries. The framework is anticipated to help identify factors explaining the decline and variability in effectiveness of interventions and assessing the prospects of implementation effectiveness, when spreading interventions. We do not intend to only develop another stand-alone implementation framework but one that can be used in conjunction with existing frameworks. The framework can be honed and validated in future empirical research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084485.