During building renovation or demolition, asbestos fibers can be released which can contaminate the environment, leading to potential occupational health and public health concerns. Strict asbestos abatement procedures and regulations are in place to mitigate this risk, which involve sealing the worksite and depressurizing it relative to the outdoor environment (i.e., indoor pressure lower than the outdoor pressure) using mechanical ventilation. However, the depressurization of the containment can be breached by the effects of the wind. Hence, it is essential to identify which wind conditions are problematic and how to prevent their effects. To conduct corresponding laboratory measurements, it is first required to scale down the building and its containment zone including a working mechanical ventilation system. This paper presents an innovative methodology for conducting reduced-scale experiments on buildings equipped with mechanical ventilation systems for contaminant containment. The methodology, here explained in the context of asbestos abatement, could also be applied to any other type of particulate pollutant. The methodology of this research study includes the design of a mechanical ventilation system for depressurization; a method to scale down the building and the ventilation system for testing in a wind tunnel; and 3D steady Reynolds averaged Navier-Stokes (RANS) simulations for optimizing the positioning of the ventilation components. The methodology is applied for a single-zone building including its ventilation system, which is found to achieve the targeted indoor depressurization of −40 Pa, making it ready for wind tunnel tests.