Ultrasound　(US)-based　disinfection　involves　the　disruption　of　cell　membranes,　oxidation　of　active　free　radicals,　as　well　as　hotspot　heating,　either　individually　or　in　combination.　Various　factors　can　affect　US　efficiency　for　inactivating　microbes.　However,　only　a　few　studies　have　discussed　the　use　of　US　for　microbial　inactivation　via　response　surface　methodology.　Here,　we　evaluated　the　potential　of　US　for　the　disinfection　of　water　supply　or　the　elimination　of　drinking　water　residues.　Moreover,　the　effects　of　US　inactivation　parameters,　such　as　energy　density,　sonication　time,　and　US　device　duty　cycle　on　reduction　in　total　bacterial　(TB)　count　and　total　coliform　(TC)　count　were　investigated　and　optimized.　The　results　indicated　that　the　optimal　inactivation　condition　was　achieved　at　an　energy　density　of　8.30　W/mL,　a　sonication　time　of　950　s,　and　a　duty　cycle　of　0.7:0.3.　Under　optimal　conditions,　the　experimental　values　of　TB　and　TC　inactivation　efficiency　were　47.26%　+/-　4.35%　and　39.23%　+/-　2.27%,　respectively,　while　the　predicted　values　were　46.57%　and　38.65%,　respectively.　The　models　developed　here　helped　to　predict　the　effectiveness　of　inactivation　efficiency　to　a　＇sufficiently　applicable＇　extent.　Under　the　optimized　conditions,　US　has　high　potential　as　an　effective　disinfection　method,　as　shown　by　energy　efficiency　analysis.