The aim of this study is to investigate the feasibility of identifying and applying quantitative imaging features computed from ultrasound images of athymic nude mice to predict tumor response to treatment at an early stage. A computer-aided detection (CAD) scheme with a graphic user interface was developed to conduct tumor segmentation and image feature analysis. A dataset involving ultrasound images of 23 athymic nude mice bearing C26 mouse adenocarcinomas was assembled. These mice were divided into 7 treatment groups utilizing a combination of thermal and nanoparticle-controlled drug delivery. Longitudinal ultrasound images of mice were taken prior and post-treatment in day 3 and day 6. After tumor segmentation, CAD scheme computed image features and created four feature pools including features computed from (1) prior treatment images only and (2) difference between prior and post-treatment images of day 3 and day 6, respectively. To predict tumor treatment efficacy, data analysis was performed to identify top image features and an optimal feature fusion method, which have a higher correlation to tumor size increase ratio (TSIR) determined at Day 10. Using image features computed from day 3, the highest Pearson Correlation coefficients between the top two features selected from two feature pools versus TSIR were 0.373 and 0.552, respectively. Using an equally weighted fusion method of two features computed from prior and post-treatment images, the correlation coefficient increased to 0.679. Meanwhile, using image features computed from day 6, the highest correlation coefficient was 0.680. Study demonstrated the feasibility of extracting quantitative image features from the ultrasound images taken at an early treatment stage to predict tumor response to therapies.