AbstractUsing results from 57 large‐scale physics‐based fault‐rupture and wave propagation simulations, this research aims to evaluate the seismic risk, loss, and resilience of more than 16,000 reinforced concrete buildings in the Zeytinburnu district of Istanbul, Turkey. For each building and under each earthquake scenario, the spatially varying site‐specific simulated ground motions were used for performing three‐dimensional nonlinear time‐history analyses. The resulting structural responses—such as peak story drift ratios (PSDR) and peak floor accelerations (PFAs)—were utilized to conduct three region‐scale tasks: (i) building‐ and site‐specific seismic fragility analysis for both structural and nonstructural components of each building; (ii) intensity‐based seismic loss assessment using the FEMA P58 methodology and Monte Carlo simulations; and (iii) resilience evaluation based on the expected time of recovery predicted through FEMA P58. Moreover, both inertial and kinematic soil–structure interaction (SSI) effects were considered using a substructuring method for all three tasks. Site‐specific soil properties were utilized to compute the coefficients of soil springs and dashpots, as well as the foundation input motions. The SSI effects were investigated by comparing the fragility, loss, and resilience indices obtained with and without considering SSI.