Chemo-radiation therapy is a principal modality for the treatment of head and neck cancers, and its efficacy depends on the interaction of tumor oxygen with free radicals. In this study, we adopted a novel hybrid diffuse optical instrument combining a commercial frequency-domain tissue oximeter (Imagent) and a custom-made diffuse correlation spectroscopy (DCS) flowmeter, which allowed for simultaneous measurements of tumor blood flow and blood oxygenation. Using this hybrid instrument we continually measured tumor hemodynamic responses to chemo-radiation therapy over the treatment period of 7 weeks. We also explored monitoring dynamic tumor hemodynamic changes during radiation delivery. Blood flow data analysis was improved by simultaneously extracting multiple parameters from one single autocorrelation function curve measured by DCS. Patients were classified into two groups based on clinical outcomes: a complete response (CR) group and an incomplete response (IR) group with remote metastasis and/or local recurrence within one year. Interestingly, we found human papilloma virus (HPV-16) status largely affected tumor homodynamic responses to therapy. Significant differences in tumor blood flow index (BFI) and reduced scattering coefficient (μs’) between the IR and CR groups were observed in HPV-16 negative patients at Week 3. Significant differences in oxygenated hemoglobin concentration ([HbO2]) and blood oxygen saturation (StO2) between the two groups were found in HPV-16 positive patients at Week 1 and Week 3, respectively. Receiver operating characteristic curves were constructed and results indicated high sensitivities and specificities of these hemodynamic parameters for early (within the first three weeks of the treatment) prediction of one-year treatment outcomes. Measurement of tumor hemodynamics may serve as a predictive tool allowing treatment selection based on biologic tumor characteristics. Ultimately, reduction of side effects in patients not benefiting from radiation treatment may be feasible.