Despite the best efforts in air-purification, airborne infectious diseases do and will continue to spread due to continuous emission of bioaerosols by the host/infected person. To tackle the rapid spread of airborne infectious diseases, a shift in focus from air-purification to bioaerosol disinfection/ decontamination is urgently needed. In this work, we studied a cold plasma ionizer (CPI) and electrostatic precipitator (ESP)-coupled CPI (CPI-ESP) for disinfection and cleaning of bioaerosols. Using porcine respiratory coronavirus (PRCV) and E. coli in a testing chamber, we demonstrated that CPI coupled with ESP is an effective technology for inactivating aerosolized microorganisms and microorganisms spread on surfaces. In addition, we have demonstrated the efficiency of a CPI-ESP coupled device for disinfection of naturally occurring airborne microbials in a few indoor settings (i.e., an living room, a discussion room, a schoolroom and an office) to determine the treatment duration- and human activity-dependent efficacy. To understand the disinfection mechanism, we conduced fluorescence microscopy study to reveal different degree of bacteria cell membrane damage under CPI treatment.