Here we describe the study of the seismic behavior of the bridgehead of Nanjing Yangtze River Bridge after the strengthening of its infilled walls. In this study, we proposed a double-strut model in consideration of the cracked higher infilled walls for rare earthquake analysis. In addition, an accurate approach to simulating the structure after the strengthening of the infilled walls was also developed. Using SAP2000, structural computing models used for the analysis of frequent earthquakes, fortification earthquakes and rare earthquakes were established. The seismic behaviors of the bridgehead structure before and after the strengthening of the infilled walls were compared. Furthermore, in order to study the seismic response of the bridgehead, a real earthquake happening in 1974 was introduced in the analysis and compared with the El-Centro wave. The study results showed that 1) the seismic behavior of the bridgehead after the strengthening of the infilled walls was improved remarkably. The peak value of displacement responses decreased by 8%~23% and the inter-story displacement angle responses decreased by 12%~22%; 2) the inter-story displacement angles in the X direction and the Y direction both met standard requirements under fortification earthquake action; 3) the cracking of the infilled walls in the rare earthquake reduced the torsional stiffness of the bridgehead structure, but it was improved after the infilled walls were strengthened, which, therefore, avoided the torsional vibration of the structure in the earthquake effectively. Furthermore, the difference of the results using two different earthquake waves was about 3%~21%, and the positions of the peak responses of the bridgehead were a little different. Thus, it is suggested that more than one earthquake waves should be selected to analyze the seismic behavior of a bridgehead structure. The study results could provide a reference for the seismic strengthening of similar historical reinforced concrete buildings.