Objective Establishing animal model of Vibrio vulnificus (V. vulnificus) early infection via respiratory tract, to observe the survival, pathological changes of target organs and the expression changes of inflammatory cytokines in model mice, and to provide references for the relevant prevention and treatment strategies. Methods A total of 24 healthy female BALB/c mice (8 to 10 weeks old) were randomly divided into 4 groups (6 mice per group), including control group and three infection groups (low, medium and high concentration of infection, respectively), based on which the V. vulnificus infection models were established by intranasal administration. The survival statistics, status of defecation, hair and respiration as well as mental state of mice were monitored during 0-12 h early infection progress. Hematoxylin-eosin (HE) staining was performed on the important organs of mice to analyze the pathological manifestations, and immunohistochemical staining was used to detect the expression of interleukin (IL)-6, IL-10, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in the target organs. Mouse inflammation panel combined with flow cytometry was used to further detect the changes of multiple inflammatory and anti-inflammatory cytokines in serum. Results V. vulnificus infection via respiratory tract caused mice deterioration in survival rate, defecation, hair status, respiratory tract and mental state within 12 h. HE pathological analysis showed inflammatory cell infiltration and cell necrosis in ileum, lung, liver and spleen of mice in different infection groups, and the injury was much severer in high concentration of infection group. Immunohistochemical results reflected the positive expression rates of IL-6, IL-10, IFN-γ and TNF-α in ileum, lung, liver and spleen of mice in medium and high concentration of infection groups were significantly higher than those in control group (P<0.05). The results of mouse inflammation panel and flow cytometry showed that compared with the control group, the expression levels of TNF-α and monocyte chemotactic protein (MCP)-1 in all three infection groups were significantly increased (P<0.05), and the expression level of IL-27 significantly decreased (P<0.05); the expression levels of IL-1β, IL-6, IL-17A and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly increased in medium and high concentration of infection groups (P<0.05); the expression levels of IL-1α, IL-23, IL-12p70 and IFN-γ were significantly increased in high concentration of infection group (P<0.05). Conclusions V. vulnificus infection progressed rapidly through respiratory tract in mice, and lung, intestine, liver and spleen were major target organs. Accompanied by increased secretion of multiple serum inflammatory cytokines, V. vulnificus infection through respiratory tract might further causes severe inflammatory reaction in hosts.