The paper explores the possibilities of the structural and functional transformation of blocks in the historical center of Zagreb as a part of modernization after many years of neglect as well as earthquakes in 2020. The research aims to determine how the existing block tissue corresponds with the needs of today’s residents and the possibility of its improvement. The historical circumstances in which the blocks were formed and underwent the most significant changes and modern processes that affect the state and value are determined. There is a special focus on the interior of the block (courtyards), as well as on the spaces on the ground floors of street facades, where numerous, unexplored changes can be observed. The findings provide starting points for desirable structural–functional transformations of blocks and stem from the synthesis and interpretation of knowledge from four interrelated parts of the research. The characteristics of blocks have changed during city development stages, as depicted by an analysis and graphic interpretation of historical maps and urban plans (1864–2021). Influences of modern processes on changes of the city are determined on the basis of the synthesis of previous research from different interdisciplinary points of view; a detailed analysis of the structural–functional changes is conducted on the example of three selected blocks. Transformation models for three selected blocks are proposed.