High Intensity Focused Ultrasound (HIFU) is a promising means of non-invasive thermal therapy. However, monitoring and assessment challenges for HIFU thermal therapy remain. Quantitative ultrasound (QUS) has been hypothesized to be sensitive to changes in tissue microstructure due to therapy. In this work, QUS assessment of thermally treated MAT tumors was examined. MAT tumors were grown in rats and the tumors were treated by heating in a saline bath or by direct HIFU exposure. For the saline bath experiments, MAT tumors were excised and cut into two halves. One half of each tumor was treated in 60 °C saline for 10 minutes and the other half remained untreated. A single-element transducer was used to scan the two halves of the tumors. RF backscatter data was collected and QUS estimates were obtained. The QUS parameters obtained from the backscatter were the effective acoustic concentration (EAC) and the effective scatterer diameter (ESD). The scans revealed an 8% increase in ESD and a 4 dB decrease in EAC on average with treatment. A second set of MAT tumors was exposed directly to HIFU. Before and after exposure, a tumor was scanned with two separate clinical array systems. QUS estimates from untreated tumors had good agreement between the clinical systems and the single-element scans. Comparison of QUS images from before and after HIFU therapy revealed that the largest changes in QUS parameters corresponded to visible brightening in the B-mode image acquired during the scans. Histological changes were observed between untreated and treated cases for both experiments and related to changes in QUS parameters.