Background Systems Thinking (ST) has recently been promoted as an important approach to health systems strengthening. However, ST is not common practice, particularly in Low- and Middle-Income Countries (LMICs). This paper seeks to explore the barriers that may hinder its application in the Eastern Mediterranean Region (EMR) and possible strategies to mitigate them. Methods A survey consisting of open-ended questions was conducted with a purposive sample of health policymakers such as senior officials from the Ministry of Health (MoH), researchers, and other stakeholders such as civil society groups and professional associations from ten countries in the region. A total of 62 respondents participated in the study. Thematic analysis was conducted. Results There was strong recognition of the relevance and usefulness of ST to health systems policy-making and research, although misconceptions about what ST means were also identified. Experience with applying ST was very limited. Approaches to designing health policies in the EMR were perceived as reactive and fragmented (66%). Commonly perceived constraints to application of ST were: a perceived notion of its costliness combined with lack of the necessary funding to operationalize it (53%), competing political interests and lack of government accountability (50%), lack of awareness about relevance and value (47%), limited capacity to apply it (45%), and difficulty in coordinating and managing stakeholders (39%). Conclusion While several strategies have been proposed to mitigate most of these constraints, they emphasized the importance of political endorsement and adoption of ST at the leadership level, together with building the necessary capacity to apply it and apply the learning in research and practice.