Introduction Non-communicable diseases (NCDs) are the leading cause of mortality in the Eastern Mediterranean Region (EMR), driven largely by modifiable behavioral and metabolic risk factors such as unhealthy diet, physical inactivity, tobacco use, and obesity. Innovative and context-sensitive interventions are increasingly recognized as essential to address these challenges, particularly in settings characterized by sociocultural constraints, fragile health systems, and humanitarian crises. This systematic review aimed to examine evidence on innovative approaches for addressing NCD risk factors in the EMR. Methods A systematic review was conducted in accordance with PRISMA guidelines. Electronic databases (PubMed/MEDLINE, Scopus, Web of Science, and Embase) were searched for studies published between January 2000 and December 2025. Eligible studies evaluated innovative or context-sensitive interventions targeting modifiable NCD risk factors in EMR populations and included randomized controlled trials, quasi-experimental studies, natural experiments, and field trials. Data were extracted using a standardized form, and methodological quality was assessed using the Mixed Methods Appraisal Tool (MMAT). Due to heterogeneity, findings were synthesized narratively. Results Ten studies met the inclusion criteria, with most conducted in Tunisia and additional evidence from Jordan, Palestine, Iran, and Saudi Arabia. Interventions included integrated mental health and NCD programs, community-based initiatives, workplace interventions, culturally adapted health promotion programs, and system-level incentive models. These interventions demonstrated improvements in cardiometabolic outcomes, dietary behaviors, and physical activity, although effects varied across settings. Tobacco-related outcomes were inconsistent, and composite cardiovascular risk scores showed limited improvement. No studies implemented interactive digital health platforms; one study used pedometers as passive monitoring tools. Conclusions Innovative, community-based, culturally responsive, and multisectoral interventions show promise in addressing NCD risk factors in the EMR. However, evidence remains limited, geographically concentrated, and methodologically heterogeneous. The absence of evaluated digital health interventions highlights a gap in the current evidence base. Future research should prioritize rigorous designs, scalable models, and evaluation of digital health strategies to strengthen NCD prevention across the region. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251064273 .
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