The energy-efficient inactivation of airborne antibiotic resistance genes (ARGs) and virulence genes was seldom investigated in full-scale ventilation systems. This study examined the potential of UV disinfection to inactivate two types of chromosome- or plasmid-encoded ARGs (mecA and amp) and one chromosomal virulence gene (tst1) within two host bacterial species: Staphylococcus aureus and Escherichia coli. UV185+254 disinfection exhibited dual damages (i.e., physical by 254 nm UV and oxidative by the produced ozone) on those target genes, resulting in relatively strong adaptability to temperature and low electrical energy per order in specific gene removal (down to 1 kJ m−3). It was found that the disinfection efficiency of target genes was up to 2 orders of magnitude lower than that of the host bacteria. The target genes with more bases and higher weighted bipyrimidine content were more susceptible to UV185+254 treatment. Thicker cell walls and plasmid carriers prominently hindered UV185+254 deactivation, requiring larger radiation power to enhance the gene removal efficiency in bioaerosols.