The response of mid-rise reinforced concrete (RC) buildings in Mexico City after the 2017 Puebla Earthquake is assessed through combined field and computational investigation. The Mw 7.1 earthquake damaged more than 500 buildings where most of them are classified as mid-rise RC frames with infill walls. A multinational team from Colombia, Mexico, and the United States was rapidly deployed within a week of the occurrence of the event to investigate the structural and nonstructural damage levels of over 60 RC buildings with 2–12 stories. The results of the study confirmed that older mid-rise structures with limited ductility capacity may have been shaken past their capacity. To elucidate the widespread damage in mid-rise RC framed structures, the post-earthquake reconnaissance effort is complemented with inelastic modeling and simulation of several representative RC framing systems with and without masonry infill walls. It was confirmed that the addition of non-isolated masonry infills significantly impacts the ductility capacity and increases the potential for a soft-story mechanism formation in RC frames originally analyzed and designed to be bare systems.