This study investigated, using validated computational fluid dynamics techniques, the actual performance of portable air purifiers for reducing the infection risks of airborne respiratory diseases such as COVID-19, by properly installing air purifiers in complicated large public spaces of primary concern, such as restaurants and ballrooms. The research results reveal that portable air purifiers with HEPA filtration provide an effective solution to help mitigate virus-carrying particles/droplets in large spaces where the central air conditioning system with HEPA filtration may not provide adequate dilution and/or effective ventilation. Deploying portable air purifier changes the local flow directions, and thus, reduces the cross-table airflows that may enhance the possibility of cross-infection. A field experiment was further conducted in a restaurant and a ballroom to verify the on-site performance. This study indicates that each space is unique in furniture, occupant and system layouts and capacities, and thus, requires individualized investigation of appropriate purifier number, capacities, and locations. Flexible solutions such as portable air purifiers are important and low-cost supplements to more elaborate solutions installed in central air systems.