We presume that severe secondary Pseudomonas aeruginosa (PA) infection can lead to cellular senescence in lung tissue and thus contribute to high mortality. We established a two-hit mouse model using cecal ligation and puncture (CLP) followed by sublethal PA lung infection. In lung tissue, increased infiltration of inflammatory cells, elevated lung injury and augmented cellular senescence was shown in mice with CLP followed by sublethal PA infection, and these observations reached a higher rank when higher (H) loads PA (PAO1) were administered to CLP mice (CLP + PAO1-H). Accordingly, oxidative stress-related element gp91phox and inflammation regulator NF-κB were greatly activated in CLP + PAO1-H mice compared to others. There was no obvious inflammation or cellular senescence in sham control, PAO1-infected mice. Consequently, CLP + PAO1-H mice had the highest expression levels of inflammatory cytokines IL-6, TNFα and iNOS among those groups. There was lower bacterial clearance ability in CLP + PAO1-H mice than in other mice. CLP + PAO1-H only had approximately 10% survival after 7 days of investigation and was much lower than others. In conclusion, higher mortality due to increased lung inflammation and cellular senescence are observed in mice with increased loads of PA infection secondary to CLP.