RC frames with infill walls account for a large portion of building stocks, particularly for low to medium-rise buildings in Asia and other parts of the world. Based on past studies and the observed responses of these buildings during earthquakes, infill walls play an important role in the structural response of buildings under seismic excitations. Disregarding their influences on the seismic design and evaluation of structures could be potentially dangerous. However, the interaction between the frame and the infill wall is very complex. Therefore, a reliable numerical model is necessary. A novel multi-strut macro finite element model was used in this study to perform vulnerability assessment of an example low-rise RC frame. Data-driven empirical formulas for predicting the equivalent strut parameters were developed and calibrated based on a comprehensive experimental database and regression analysis. The application of the proposed approach for an RC frame simulation was examined.