Objective To observe if fluoxetine has a potency to inhibit the progression of Lewis lung cancer by combining the fluoxetine and cisplatin to treat the mice bearing Lewis lung cancer with depression. Methods We developed a mouse model of Lewis lung cancer with depression which was intervened with cisplatin and fluoxetine, and the indicators related to cancer and depression were tested. Social interaction test was used to measure the behavioral changes of the depressed model mice. The serum cortisol and IL-6, BDNF mRNA in the hippocampus, and NF-κB and VEGF in the tumor tissue were selected for investigation and comparison. Results The mice which were induced by social defeat exhibited social avoidance behavior in the social interaction test. The cortisol and IL-6 level in both combination groups was decreased compared with that in the model group (P<0.05), and the cortisol and BDNF mRNA in the combination group increased signifuicantly (P<0.05). There were no statistically significant differences in the tumor weight, NF-κB and VEGF in tumor tissues between the single and combination groups (P>0.05). Conclusions Fluoxetine has antidepressant effect by decreasing the high level of serum cortisol and promoting the BDNF mRNA expression in the hippocampus. However, fluoxetine is not found to have the potency to inhibit the expression of NF-κB related with the progression of tumor.