The incidence rate of diagnosed thyroid cancer has increased over the last decades. Although ultrasonic imaging has increased the malignancy detection rate, current ultrasonography markers do not provide a sufficient level of diagnostic accuracy to replace the fine needle aspiration biopsy. Recently, studies have reported that significant differences were observed in the values of quantitative ultrasound (QUS) parameters derived from a thyroid cancer rodent model between normal/benign and malignant tissues. In the present study, the performance of a multi-parametric classification for the differentiation of thyroid cancer in this rodent model has been evaluated. The experimental database consisted of 32 mice having different predispositions to developing thyroid abnormalities; 6 of them developed thyroid cancer papillary carcinoma (PTC), 5 follicular variant papillary thyroid carcinoma (FV-PTC), 6 developed benign tumors (c-cell adenoma) and 15 did not develop any thyroid abnormalities. Backscattered data was obtained from excised thyroid tissues using a 40 MHz, f/3 single element transducer. A total of five QUS parameters were derived from the ultrasound data: two from backscatter coefficients (i.e., the effective scatterer diameter (ESD) and effective acoustic concentration (EAC)), two from envelope statistics (i.e., the μ and k parameters), and one from ultrasound attenuation (i.e., attenuation coefficient slope). A two-class classification between normal/benign and malignant cases was performed using linear discriminant analysis with both one- and two-dimensional feature spaces. When using a two-dimensional feature space, it was found that the combination of EAC and 10/μ resulted in both a sensitivity and specificity of 100%.