〔Abstract〕 Objective To investigate the role of Interleukin (IL)-17A in acute inhalational pneumonia induced by the highly drug-resistant and hypervirulent Staphylococcus aureus strain USA300-R in mice. Methods An acute inhalational pneumonia model was established in mice using an aerosolized pulmonary delivery technique. RNA sequencing (RNA-seq) and enzyme-linked immunosorbent assay (ELISA) were employed to examine the expression dynamics of Il17a mRNA and IL-17A protein, respectively, in the lungs of infected mice. Il17a knockout ( Il17a -/-) mice were generated using CRISPR/Cas9 gene editing technology. The survival rate, body weight, bacterial load in lung tissue, and histopathological changes were compared between Il17a -/- and wild-type (WT) mice following inhalational infection with USA300-R. Results 12 hours after USA300-R infection, compared to pre-infection, the expression level of Il17a mRNA in lung tissue and the level of IL-17A protein in bronchoalveolar lavage fluid (BALF) increased by approximately 50-fold ( P< 0.01) and 6-fold ( P< 0.001), respectively. Compared to WT mice, Il17a -/- mice exhibited approximately 10-fold higher bacterial loads in lung tissue at both 12 and 24 hours post-infection ( P< 0.001， P<0.05). However, they showed significantly attenuated lung histopathological injury, reduced alveolar wall thickening, markedly decreased neutrophil infiltration, and an approximately 50% improvement in survival rate ( P < 0.05). Conclusion In acute Staphylococcus aureus USA300-R inhalational pneumonia, IL-17A contributes to bacterial clearance by recruiting neutrophils; however, excessive neutrophil infiltration exacerbates pulmonary inflammation and injury, reduces survival rates, and represents a potential therapeutic target.