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The gut-brain axis has been shown to play a vital role in the prognosis and recovery of ischemic stroke (IS), which is associated with gut microbiota dysfunction and changes in the gastrointestinal system and epithelial barrier integrity. In turn, gut microbiota and its derived metabolites can influence stroke outcomes. In this review, we first describe the relationship between IS (clinical and experimental IS) and the gut microbiota. Second, we summarize the role and specific mechanisms of microbiota-derived metabolites in IS. Further, we discuss the roles of natural medicines targeting the gut microbiota. Finally, the potential use of the gut microbiota and derived metabolites as a promising therapeutic opportunity for stroke prevention, diagnosis, and treatment is explored.