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In this paper, I explore the various qualitative methodological approaches to conducting a within-case comparative analysis of environmental health politics and policy within megacities in developing nations, such as Mexico City, São Paulo, Delhi, Beijing, and Jakarta. Megacities are defined as cities with a population exceeding 10 million inhabitants and exhibiting a high level of inequalities in income, infrastructure, and access to air, water, and infrastructural services—the outcomes of interest in this study. This article maintains that while a considerable amount of sub-national comparative research has gone into comparing urban-rural areas, especially within advanced industrialized nations, we know little about comparative methodological approaches within megacities, particularly in developing nations. By proposing a new methodological approach based on the integration of institutional change theory and global health diplomacy, this paper adds to recent calls for political scientist to conduct these kinds of urban-level comparisons in developing nations with the objective of providing new methodological and political insights.