This paper investigates the behavior of unreinforced masonry (URM) infills in reinforced concrete (RC) moment resisting frames (RC-MRFs) subjected to bidirectional seismic excitations. Three-dimensional special RC-MRFs with heights of 4, 8, and 12 stories were designed and modeled, followed by nonlinear time history analyses of the frames under 20 far-field scaled ground motion records. To evaluate the influence of infill configuration on the dynamic response of the RC-MRFs, three different infill layouts in plan (two symmetrical and one asymmetrical layout) were considered. A total of 480 time-history analyses were performed, considering different heights, plan configuration, and ground motion excitation. Furthermore, to assess the behavior of masonry infills under bidirectional loading and to consider the capacity interaction of URM infills under in-plane and out-of-plane loads, an idealized single diagonal strut model was employed for infill simulation in the OpenSees platform. The analyses were conducted for every frame under unidirectional and bidirectional ground motions. According to the analysis results, the failure of masonry infills in the RC-MRFs was mainly due to the in-plane interaction of the frame and URM wall, resulting in collapse of the infill walls of the bottom- and mid-stories of the frames that underwent relatively higher inter-story drifts. Moreover, depending on the building height and infill configuration, infills in frames subjected to bidirectional loading experienced higher levels of damage (up to 35%). The significant bidirectional effect of loading on the masonry infills needs to be addressed in the design codes and considered in the design process.