Strong aftershocks generally occur following a significant earthquake. Aftershocks further damage buildings weakened by mainshocks. Thus, the accurate and efficient prediction of aftershock-induced damage to buildings on a regional scale is crucial for decision making for post-earthquake rescue and emergency response. A framework to predict regional seismic damage of buildings under a mainshock–aftershock (MS–AS) sequence is proposed in this study based on city-scale nonlinear time-history analysis (THA). Specifically, an MS–AS sequence-generation method is proposed to generate a potential MS–AS sequence that can account for the amplification, spectrum, duration, magnitude, and site condition of a target area. Moreover, city-scale nonlinear THA is adopted to predict building seismic damage subjected to MS–AS sequences. The accuracy and reliability of city-scale nonlinear THA for an MS–AS sequence are validated by as-recorded seismic responses of buildings and simulation results in published literature. The town of Longtoushan, which was damaged during the Ludian earthquake, is used as a case study to illustrate the detailed procedure and advantages of the proposed framework. The primary conclusions are as follows. (1) Regional seismic damage of buildings under an MS–AS sequence can be predicted reasonably and accurately by city-scale nonlinear THA. (2) An MS–AS sequence can be generated reasonably by the proposed MS–AS sequence-generation method. (3) Regional seismic damage of buildings under different MS–AS scenarios can be provided efficiently by the proposed framework, which in turn can provide a useful reference for earthquake emergency response and scientific decision making for earthquake disaster relief.