Cities, and therefore neighborhoods, are under constant change. Neighborhood changes may affect residents’ health in multiple ways. The Heart Healthy Hoods (HHH) project studies the association between neighborhood and residents’ health. Focusing on a middle–low-socioeconomic neighborhood in Madrid (Spain), our aim was to describe qualitatively its residents’ perceptions on the urban changes and their impacts on health. We designed a qualitative study using 16 semi-structured interviews including adult residents and professionals living or working in the area. Firstly, we described the perceived main social and neighborhood changes. Secondly, we studied how these neighborhood changes connected to residents’ health perceptions. Perceived major social changes were new demographic composition, new socio–cultural values and economic changes. Residents’ negative health perceptions were the reduction of social relationships, increase of stress and labor precariousness. Positive health perceptions were the creation of supportive links, assimilation of self-care activities and the change in traditional roles. Neighborhood changes yielded both negative and positive effects on residents’ health. These effects would be the result of the interrelation of different elements such as the existence or absence of social ties, family responsibilities, time availability, economic resources and access and awareness to health-promoting programs. These qualitative research results provide important insight into crafting urban health policies that may ultimately improve health outcomes in communities undergoing change.