Despite the widespread use of reinforced concrete in Italy, particularly after the Messina earthquake of 1908, its application was not formally regulated until R.D.L. n. 2229 of 1939. This regulatory gap, combined with a strong urban expansion especially within industrial cities, led to the construction of numerous unregulated mixed masonry-RC buildings, combining masonry walls with RC frames in various configurations. These remain poorly documented and largely unknown, making their seismic vulnerability difficult to assess. This paper investigates the seismic behavior of mixed masonry–reinforced concrete (RC) buildings within the historical residential stock of Genoa, Italy. Through archival research, historical documentation, and non-destructive surveys, the study investigates construction techniques and materials that influence the seismic response of hybrid buildings. A representative case study is selected and modeled in six different possible configurations using the 3Muri software, ranging from URM with timber floors to fully RC-framed systems. Nonlinear static (pushover) analyses are carried out to compare global seismic performance and local wall behavior across all models. Results show that early hybrid configurations with structural masonry integrated into RC frames provide a superior balance of strength, stiffness, and ductility. Later RC-dominant models, though more flexible, tend to underperform due to limited masonry contribution.