The coronavirus (COVID-19) pandemic has brought immense challenges to the natural and built environment to develop an antivirus-enabled model for reducing potential risks of spreading the virus at varied scales such as buildings, neighborhoods, and cities. Spatial configurations of structures may hinder or assist the spread of viruses in the built environment. In this study, we have hypothesized that suitable air ventilation in historic buildings may enhance the built environment to combat the spreading of infectious viruses. To provide such quantitative shreds of evidence, we have generated and estimated an integrated model to summarize obtained information by considering natural ventilation, wind speed, inflow and outflow, wind direction, and forecasting the associated risks of airborne disease transmission in a historical building (i.e., the Hazzazi House in particular). Intrinsically, the results have demonstrated that the effectiveness of natural ventilation has directly influenced reducing the risks of transmitting airborne infectious viruses for the selected heritage building in Jeddah (Saudi Arabia). The adopted methods in this research may be useful to understand the potentials of conserving old heritage buildings. Consequently, the results demonstrate that natural air ventilation systems are critical to combat the spread of infectious diseases in the pandemic.