Nonthermal plasma and ultrasound are two techniques capable of microorganism inactivation in a liquid phase. However, the interaction between the two techniques is not yet understood. In this study, an ultrasound-assisted plasma (USaP) technique by combining the two means is proposed. A lab-scale USaP system was designed and experimentally tested. The inactivation experiments were conducted with various conditions of two types of electrode layout (submerged and hybrid reactors), aeration or not, and two microorganism species E. coli and yeast. For a 30-min treatment, the inactivation efficiencies with no aeration were 2-, 2-, and 6-log reductions for ultrasound, plasma, and ultrasound-assisted plasma, respectively; and with aeration were 2-, 6-, and 6-log reductions, respectively. The aeration greatly enhanced the inactivation efficiency for the plasma but not for the ultrasound or the ultrasound-assisted plasma. The influences of electrode layout and microorganism species were insignificant on the inactivation efficiency. On the other hand, for a submerged reactor without aeration, the inactivation efficiency achieved with ultrasound-assisted plasma (ηUSaP) was not only greater than ηultrasound or ηplasma, but also greater than the summation of ηultrasound and ηplasma. Namely, a synergistic effect of ultrasound-plasma combination on the inactivation was observed. No such synergistic effect was observed in a hybrid reactor or in aeration cases. The synergism is speculatively a virtue of the ultrasonic-generated bubbles that easily induce plasma discharges, and thus enhance microorganism inactivation in water.