Low-intensity ultrasound (LIUS) combined with chemotherapy is an innovative modality for cancer treatment, but its effect on orthotopic carcinoma remains unknown. Our previous study revealed that LIUS enhanced the growth inhibitory effects of several chemotherapeutic drugs in nude mice with transplanted tumors. In the present study, we used 7,12-dimethylbenz(alpha)anthracene to induce orthotopic tongue carcinogenesis in hamsters. We used the first-line chemotherapy drug for tongue cancer, carboplatin (CBP) in combination with LIUS to investigate the synergistic effect. The results revealed that LIUS combined with low-dose CBP enhanced the inhibitory effects of CBP on tumor growth, prolonged survival, and did not increase the incidence of side-effects. It also enhanced the inherent DNA damage caused by CBP, suppressed the expression of the DNA repair proteins O6-methylguanine DNA methyltransferase (MGMT) and Chk1, and increased the expression of DNA damage-inducible protein GADD45α. Furthermore, compared with CBP alone, LIUS combined with CBP reduced the expression of cyclin D1 and cyclin B1, induced the expression of caspase-3, cleaved caspase-3, caspase-8, Bax, and Bak, and inhibited the expression of Bcl-2. Examination of clinical samples revealed that MGMT, Chk1, and Gadd45α were higher in OTSCC than in adjacent normal tissue. Hence, our results indicated that LIUS enhanced the ability of low-dose CBP to damage DNA in an orthotopic hamster model of tongue cancer, induced apoptosis, inhibited tumor growth and progression, while it did not increase the toxic side-effects of the drug, suggesting additional clinical benefits for patients treated with the combination of CBP with LIUS.