Background: To deal with the rising prevalence and death rate of non-communicable diseases, the WHO designed a package of essential interventions for non-communicable diseases for low- and middle-income countries. This review aimed to identify the barriers and facilitators of the implementation of this program. Methods: The electronic databases of PubMed, Scopus, Web of Science, Cochrane Library, and Scientific Information Database (SID) were searched for papers without a time limit at the end of Dec 2020. Only English and Persian languages were considered. The PRISMA guideline was consulted. Results: Overall, 15 articles were selected for the final analysis out of 404 initially retrieved ones, based on inclusion/exclusion criteria and quality assessment. Thirteen articles had good quality, while 2 articles were of fair quality. Studies were published during 2014-2020. Thematic analysis was used to make sense of papers so that barriers and facilitators were categorized within 2 main themes and 7 sub-themes. Certain organizational factors including human resources, service delivery, structure, leadership/governance, data and information, resources, and financing were identified as barriers and facilitators. Knowledge and culture, and economic and social factors were identified as contextual factors. Conclusion: By considering the factors identified in this study, policymakers and health system managers can be more successful in implementing this WHO PEN and similar packages.