Glioblastoma is the most common primary brain tumor with a poor prognosis despite advances in various treatment modalities, such as radiation therapy (RT). This study compared the tumor growth inhibition effects of focused ultrasound-targeted microbubble destruction (UTMD) therapy with the RT using an orthotopic mouse glioma model. Mice were implanted with GL261 glioblastoma cells and divided into three groups: control group (no treatment); RT group (2 Gy/day, 5 days/week, 3 consecutive weeks); and UTMD group (FUS sonication in the presence of systemically injected microbubbles at the peak negative pressure of 1.5 MPa, frequency of 1.44 MHz, and 2 treatments/week for 3 consecutive weeks). Contrast-enhanced magnetic resonance imaging (MRI) was performed once every four days for measuring the tumor volume. Both UTMD and RT caused significant growth inhibition compared to the control group; however, there was no significant difference between the UTMD and RT groups. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that the number of apoptotic tumor cells in both RT and UTMD groups were significantly higher than the control group without the difference between these two groups. This study suggests that UTMD suppressed glioblastoma tumor growth and this effect was comparable with that achieved by RT.