<p>The severity and mortality rates associated with respiratory infectious diseases are notably elevated among older adults compared to younger populations. Nursing homes, which accommodate a considerable number of elderly individuals, are particularly vulnerable to disease outbreaks. This study proposes a method to assess the spatial infection risk of airborne transmission of respiratory diseases by coupling building layout and infiltrations. Field investigations were conducted to summarize nursing homes layout plan and occupants’ activity characteristics. Meteorological parameters were used to obtain the wind pressure on building surfaces through computational fluid dynamics. The building ventilation network was further developed to quantify the pathogen exposure and infection risk of occupants. Results indicated that high infectious aerosol exposure appeared in the rooms with more occupants and low ventilation rates. In nursing homes, activity rooms were the highest infectious aerosol exposure area, accounting for 38.5%–47.9% of total exposure in a standard floor, followed by bedrooms, dining halls, and offices. Self-transmission dominated pathogen aerosol transmission, with self-transmission rates exceeding 70% in most rooms. Enhancing natural ventilation was validated as effective to reduce the risk of infection from infectious aerosol exposure. The proposed infection risk assessment is beneficial for the nursing home design in order to reduce the airborne transmission of respiratory diseases.</p>