Objective To establish a mouse model of hepatocellular carcinoma pain by implanting hepa1-6 tumor tissue in the left liver lobe, and to evaluate the effectiveness of the model using behavioral, imaging, histological, and molecular biological indicators. Methods Hepa1-6 cell suspension (100–150 μL, 4×106 cells/mL) was inoculated subcutaneously in the axillary region of the forelimb. Resulting tumors were removed and cut into tissue blocks (about 1×1×1 mm3) when they protruded from the body surface. SPF male C57BL/6J mice were divided randomly into sham-implantation (sham) and model groups (n = 30 mice per group). Model mice were implanted with hepa1-6 tumor tissue blocks in the left liver lobe, while sham mice received no implant after laparotomy. General activity, body weight, and behavior in relation to back pain were evaluated. Gross liver morphology was examined by ultrasound. The structure, cell composition, and inflammatory cell infiltration of liver tissue was observed by hematoxylin/eosin (HE) staining. Activation of microglia in the spinal cord tissue was detected by immunohistochemistry (IHC). mRNA expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in the spinal cord was detected by quantitative polymerase chain reaction (qPCR), and IL-1β protein expression was detected by western blot. Results The general conditions of mice in the model group were abnormal, body weight was decreased, and the arched back pain score was significantly increased compared with the sham group (P<0.05). Ultrasound revealed protruding liver tumor tissues in the model group, and HE staining showed abnormal liver tissue structure with numerous tumor cells and inflammatory cells in the model group. Spinal cord expression of Iba1 protein detected by IHC, IL-1β, IL-6, and TNF-α mRNA expression detected by qPCR, and protein expression of IL-1β detected by western blot were all significantly increased in the model group (P<0.05). Conclusions A mouse model of hepatocellular carcinoma pain can be effectively established by implanting hepa1-6 tumor tissues in the left liver lobe. The resulting model mice show abnormal behavior in relation to back pain, abnormal liver morphology and structure, and activation of pain and inflammatory factors. This thus provides an effective animal model for the study of hepatocellular carcinoma pain, and an effective means for studying the pathogenesis of hepatocellular carcinoma pain and the effects of drug treatment.