Microbubble (MB) mediated ultrasound (US) therapy is a novel technique to non-invasively enhance cancer treatment by increasing cell membrane permeability and vascular extravasation. The objective of this experiment is to determine if MB-mediated US therapy can improve cancer therapy, specifically cisplatin or cetuximab, in head and neck cancer. In vitro experiments included combination chemotherapy and MB-mediated US therapy on head and neck cancer cell line, SCC-5, and dose curve responses to therapy. In vivo experimentation included a four week study of MB-mediated US therapy compared to current standard therapy of drug alone. Monitoring of tumor response to therapy included caliper measurements, diffusion-weighted magnetic resonance (DW-MR) imaging, and immunohistologic analysis. Anti-tumor effects increased by over 50% when combining MB-mediated US therapy with cetuximab and cisplatin (P = 0.01, P = 0.02). MB-mediated US therapy was seen to produce as additive effect by increasing localized delivery of drug in head and neck cancer. This technique shows potential for improved localized therapy in cancer.