In this study, we have designed developed the microbubbles (MBs) coated Cu-Se nanoparticles (MBs@Cu-Se NPs) was efficiently synthesized and combined with the Ultrasound for potential anticancer effects in ovarian carcinoma cells. The fabricated nanoparticles are perceived as the well-known spherical size by SEM and TEM analysis. The hydrodynamic parameters of the MBs@Cu-Se NPs confirm via DLA analysis. Further, in vitro cancer potential of the Cu-Se, MBs@Cu-Se NPs and MBs@Cu-Se NPs with Ultrasound efficiently kills the ovarian cancer cells (A2780 and CisRA2780) and reduced the cell viability in a dose-dependent manner. The MBs@Cu-Se NPs with Ultrasound displayed remarkably higher amounts of apoptosis of the ovarian cancers, which was confirmed by the various biochemical assays (AO-EB), and Hoechst-33,258 by nuclear staining. Additionally, we examined the apoptosis mechanism through the flow cytometry technique. The results reveal that the MBs@Cu-Se NPs with Ultrasound significantly induce apoptosis in both cancer cells. These results suggest that the in vitro cytotoxicity potential of MBs@Cu-Se NPs with Ultrasound combination therapy against ovarian carcinoma. Overall, new approaches of combination therapy of MBs@Cu-Se NPs with Ultrasound could be a promising alternative strategy and efficient chemotherapy as well as radiotherapy.