Elevated substance P can be utilized to predict early mortality during the first week of cerebral infarction. Whether Aprepitant, a substance P receptor blocker, could be utilized to alleviate post-stroke pneumonia is investigated in this study. Intraluminal monofilament model of middle cerebral artery occlusion (MCAO) was constructed in C57BL/6J male mice, and the relative expression of substance P was detected in collected bronchoalveolar lavage fluid (BALF) and lung tissue homogenate at 24 h, 48 h, and 72 h post-stroke. On the other hand, different concentrations of aprepitant (0.5, 1, 2 mg/kg) were atomized and inhaled into MCAO mice. Inflammation cytokines and bacterial load were detected in collected BALF and lung tissue homogenate at 72-h post-stroke, and lung injury was revealed by histological examination. Aprepitant administration decreased total proteins, total cells, neutrophils, and macrophages in BALF. The concentrations of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, interferon γ, monocyte chemoattractant protein-1, and IL-10 in lung tissue homogenates were also diminished by the administration of aprepitant. In conclusion, aprepitant could attenuate post-stroke pneumonia in mice suggesting its potential therapeutic use in the clinic.