The One Health framework has gained more importance in recent years, especially in the wake of the COVID-19 outbreak and the rise of other zoonotic diseases. However, complexities arise in the application of the One Health approach within the context of a global public health disease outbreak, especially in a culturally rich, as well as economically and politically distinctive region such as the Middle East and North Africa (MENA) region. Against this background, the chapter asks: What are the limits of the effective implementation of the One Health framework in the MENA region? This chapter examines this question through the theoretical lens of Substantive Legal Effectiveness (SLE), which suggests that law’s failure to reflect the diverse identities, needs, and contexts of all subject to the law, especially those who are already socially, economically, ethnically and/or historically marginalized, affects law’s effectiveness. While SLE offers a comprehensive and distinctive overarching framework to examine the limits of the One Health Framework in the MENA region, the chapter also draws upon the theoretical contributions of decolonial studies, specifically on the subject of decolonization of health and ecological knowledges.