Indoor air quality is an important health factor as we spend more than 80% of our time indoors. The primary type of indoor pollutant is particulate matter, high levels of which increase respiratory disease risk. Therefore, air purifiers are a common choice for addressing indoor air pollution. Compared with traditional filtration purifiers, negative ion air purifiers (NIAPs) have gained popularity due to their energy efficiency and lack of noise. Although some studies have shown that negative ions may offset the cardiorespiratory benefits of air purifiers, the underlying mechanism is still unclear. In this study, we conducted a full-scale experiment using an in vitro airway model connected to a breathing simulator to mimic inhalation. The model was constructed using computed tomography scans of human airways and 3D-printing technology. We then quantified the effects of NIAPs on the administered dose of 0.5–2.5 μm particles in the small airway. Compared with the filtration purifier, the NIAP had a better dilution effect after a 1-h exposure and the cumulative administered dose to the small airway was reduced by 20%. In addition, increasing the negative ion concentration helped reduce the small airway exposure risk. NIAPs were found to be an energy-efficient air purification intervention that can effectively reduce the small airway particle exposure when a sufficient negative ion concentration is maintained.