Objective A mouse model of influenza and Staphylococcus aureus co-infection was established to evaluate the efficacy of Tamiflu and its regulatory effect on lymphocytes and inflammatory factors. Methods (1) An influenza-Staphylococcus aureus co-infection mouse model was established by screening different titers of influenza A H1N1/PR8 virus and Staphylococcus aureus. (2) Male BALB/ c mice were selected and randomly divided into six groups. On day 0, mice were inoculated intranasally with 20 μL of influenza virus H1N1/ PR8 at a dose of 0. 25 TCID₅₀. On day 3, mice were inoculated intranasally with 20 μL of Staphylococcus aureus at a dose of 2. 5 × 10⁷ CFU. Twenty-four hours after infection with influenza virus, mice were given Tamiflu by gavage once daily for 7 days, and body weight changes were recorded every day. Mice were necropsied 24 h after the last dose. The organ index was calculated; the expression of influenza virus M gene was detected by RT-qPCR; and the contents of CD3⁺ , CD4⁺ , and CD8⁺ T lymphocytes were assessed. The levels of 13 inflammatory factors, including IL-6, were detected. The average and total pro-inflammatory values of inflammatory cytokines in each group were displayed in the form of bubble charts. Results (1) Weight loss in mice infected with 0. 25 TCID₅₀ influenza virus was relatively subtle, and the mice survived. Mouse body weight decreased steadily after co-infection with 2. 5 × 10⁷ CFU, and half of the group died; (2) thus 2. 5 × 10⁷ CFU was used as the dose for the subsequent co-infection group. In co-infected mice, body weight and thymus index decreased significantly (P<0. 05), and lung index increased significantly (P<0. 05). (3) Compared with the influenza group, the co-infection group had significantly higher M gene expression (P<0. 05). Compared with the Staphylococcus aureus group, the co-infection group’s bacterial load was significantly increased (P<0. 05). Compared with the influenza group and Staphylococcus aureus group, the absolute content of lymphocytes was significantly lower, and the content of inflammatory factors significantly increased (P<0. 05). Tamiflu treatment delayed weight loss and significantly increased the thymus index (P<0. 05), and M gene expression and bacterial load were significantly decreased, while lymphocyte content significantly increased (P<0. 05). The expression of inflammatory factors was significantly decreased (P<0. 05). A bubble diagram showed much higher average and total amounts of proinflammatory factors in the co-infection group than the other groups, and Tamiflu had a good effect after timely intervention. Conclusions In this study, we established a co-infection mouse model that conformed to the clinical characteristics of the mixed virus-bacteria infection, and Tamiflu intervention reduced subsequential damage to the body.