SAL200 is derived from a phage endolysin and is a novel candidate drug for the treatment of Staphylococcus aureus infection. We investigated the efficacy of the recombinant endolysin SAL200 in a lethal murine pneumonia model. Lethal pneumonia was established by intranasally administering a methicillin-susceptible (Newman) or methicillin-resistant (LAC) S. aureus strain into BALB/c mice. The mice were treated with a single intranasal administration of SAL200 or phosphate-buffered saline at 2 h after S. aureus infection. The survival rates were recorded until 60 h after the bacterial challenge. The bacterial loads in the lungs and blood, histopathology of lung tissues, and serum cytokine levels were evaluated following the S. aureus challenge. The SAL200-treated group and control group exhibited 90% to 95% and 10% to 40% survival rates, respectively. The bacterial loads in the lungs of the SAL200-treated group were significantly lower by ∼10-fold than those of the control group as early as 1 h after treatment. Histopathologic recovery of pneumonia was observed in the SAL200-treated mice. The cytokine levels were comparable between groups. These results suggest that direct administration of SAL200 into the lungs could be a potential adjunct treatment against severe pneumonia caused by S. aureus.