Hua-Feng-Dan is a traditional Chinese medicine used to treat ischemic stroke, but little is known about its therapeutic mechanism. This study explored whether and how the mechanism involves readjustment of gut microbiota. Rats were subjected to middle cerebral artery occlusion as a model of ischemic stroke or to sham surgery, then treated or not with Hua-Feng-Dan. The different groups of animals were compared in terms of neurological score, cerebral infarct volume, brain edema, brain and gut histopathology to assess stroke severity. They were also compared in terms of indices of intestinal barrier permeability, inflammation and oxidative stress, brain metabolites as well as composition of the gut microbiota and their metabolites. Hua-Feng-Dan significantly reduced cerebral infarct volume and brain water content and improved neurological score, ischemic brain histopathology, and gut histopathology. It partially reversed stroke-induced intestinal barrier disruption and leakage, inflammation, dyslipidemia and oxidative stress, as well as the stroke-induced increase in pathogenic gut microbiota (e.g.,