To explore the antitumor effect of transarterial chemoembolization using Doxorubicin-albumin nanoparticle loaded lipid microbubbles (mbTACE) combined with ultrasound-targeted microbubble activation (US) in rabbit VX2 liver tumor model. VX2 rabbits were assigned to 4 groups (n = 7/group): (i) saline (control); (ii) conventional TACE (cTACE); (iii) mbTACE without ultrasound activation (US-); (iv) mbTACE with ultrasound activation (US+). To assess hepatic damage, serum aspartate transaminase and alanine transaminase levels were measured on baseline and 1,3,and 7 days posttherapy. Changes of tumor volumes were segmented on MRI (baseline, 7 days posttherapy). To assess tumor necrosis, animals were euthanized on day 7, and explanted tumors were stained with hematoxylin and eosin and a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Percentage areas of viable tumors were calculated using digitalized histopathologic specimen images. estimated viable tumor volume was calculated using viable tumor fraction multiplying tumor volume on day 7 MRI. Treated groups show significant tumor suppression effect on MR compared to control group, without significant inter-treatment group difference. Tumor viable fraction and viable volume were 5.34% ± 6.54% and 89.9 mm3 ± 91.73 mm3, 17.28% ± 9.18% and 643.98 mm3 ± 758.15 mm3, 12.37% ± 8.11% and 187.01 mm3 ± 100.79 mm3, and 35.27% ± 6.46% and 1778.167 mm3± 1512.82 mm3in groups US+mbTACE, US-mbTACE, cTACE, and control (P < .001 and P < .001). Liver enzyme levels were elevated after drug delivery but recovered during follow-up. No significant differences were observed between treated groups on days 1, 3, and 7. Treatment with a combination of ultrasound activation and mbTACE showed therapeutic benefit in a liver tumor animal model.