Objective To study the core behavioral symptoms, biological indicators, and pathological changes of a mouse model of breast cancer complicated with depression induced using 4T1 breast cancer cell inoculation combined with chronic restraint stress (CRS). Methods BABL/ c mice were randomly divided into Control, Stress, Tumor, and stress combined with tumor (S+T) groups. Mice in the tumor and S+T groups were inoculated under the front legs with breast cancer 4T1 cells. After tumor formation, mice in the stress and S+T groups were subjected to CRS for 21 days. The body weight and food intake of each group were monitored during modeling. After the experiment, the occurrence of depressionlike behavior of mice in each group was evaluated by sucrose preference test, open field test, elevated plus-maze test, and forced swimming test. After the mice were decapitated, the weights and volumes of the tumors were measured.Concentrations of serum tumor markers, including carbohydrate antigen (CA199), carcinoembryonic antigen (CEA), and vascular endothelial growth factor ( VEGF), and related neurotransmitters, including 5-hydroxytryptamine ( 5-HT),norepinephrine ( NE), and corticosterone ( CORT), were determined using ELISA. HE staining was used to observe histopathological changes to the hippocampus and tumor. Results In S+T group mice, body weight and food intake were significantly decreased, tumor weight and volume were significantly increased, serum tumor marker ( CA199, CEA,VEGF) levels were significantly increased, enthusiasm and desire to explore a new environment were reduced, stress and despair behaviors were significantly increased, and levels of the serum neurotransmitters 5-HT and NE and levels of CORT were significantly increased. In addition, the cell arrangement in the tumor tissue was loose, the amount of intercellular substance decreased, the pathological nuclear classification phase was increased, the arrangement and morphology of neurons in the CA3 region of the hippocampus were disordered, and there were obvious nuclear vacuolation-like changes. Conclusions A mouse model of breast cancer complicated with depression induced by 4T1 breast cancer cell inoculation combined with CRS showed the typical dual symptoms and biological indicators of breast cancer and depression and can be used as a good reference model for experimental studies of breast cancer complicated with depression.