Since 1950, the global urban population grew from 746 million to almost 4 billion and is expected to reach 6.4 billion by mid-century. Almost 90% of this increase will take place in Asia and Africa and disproportionately in urban slums. In this context, concerns about the amplification of several neglected tropical diseases (NTDs) are warranted and efforts towards achieving effective mass drug administration (MDA) coverage become even more important. This narrative review considers the published literature on MDA implementation for specific NTDs and in-country experiences under the ENVISION and END in Africa projects to surface features of urban settings that challenge delivery strategies known to work in rural areas. Discussed under the thematics of governance, population heterogeneity, mobility and community trust in MDA, these features include weak public health infrastructure and programs, challenges related to engaging diverse and dynamic populations and the limited accessibility of certain urban settings such as slums. Although the core components of MDA programs for NTDs in urban settings are similar to those in rural areas, their delivery may need adjustment. Effective coverage of MDA in diverse urban populations can be supported by tailored approaches informed by mapping studies, research that identifies context-specific methods to increase MDA coverage and rigorous monitoring and evaluation.