As new drugs are developed in targeted therapy for advanced hepatocellular carcinoma (HCC), an accurate evaluation procedure for the therapeutic efficacy is needed. Current methods use MRI or CT based response evaluation criteria in solid tumors (RECIST) which is unsatisfactory for overlooking the functional response. We propose a new mice model of HCC for assessment of the early response to targeted therapy with contrast-enhanced ultrasound (CEUS). The major technical innovation is analysis of tumor functional characteristics using Savitzky-Golay filter (S-G filter) based CEUS quantification (SGCQ) software. In this study, mice were divided into three groups, including the control group (n(1) = 18), sorafenib treatment group (n(2) = 18) and lenvatinib treatment group (n(3) = 18). SGCQ software specialized in data smoothing was used to quantify the time, enhanced intensity and blood volume related parameters at five different time points within 14 days of therapy. Promising experimental results were obtained. From the analysis, it could detect response as early as 4th day and perfusion time (PT), mean transit time (MTT), area under the curve of tumor/adjacent parenchyma (qAUC), wash-in slope a3, the average time of perfusion (T0) were early predictors. Then, tumors were excised with histopathology performed, CD31 H-score is in correlation with parameters peak intensity (PI), enhanced intensity (EI) and area under the curve of tumor/adjacent parenchyma (qAUC). Moreover, there was no significant difference in efficacy between sorafenib and lenvatinib in both CEUS parameters and histopathology. Finally, the finding of this study proves SGCQ software to be a valid, sensitive and repeatable method for therapeutic evaluation. Quantitative and comparative studies show that sorafenib and lenvatinib, as two first-line targeted drugs, ensure the therapeutic advantages of HCC.