Cerebral ischemia-reperfusion injury (CIRI) is a secondary brain injury mediated by free radicals during the treatment of ischemic stroke. Mitochondrial DNA (mtDNA) can act as a danger signal to activate innate immune signaling pathways such as TLR9, NLRP3 inflammasome, and cGAS-STING, thereby triggering downstream inflammatory responses and inducing cell death, playing an important role in the development of CIRI. Traditional Chinese medicine (TCM) can regulate the release of mtDNA and related signaling pathways to alleviate inflammatory responses and has obvious advantages in the treatment of CIRI. This article reviews the release of mtDNA in CIRI and its related molecular mechanisms in mediating innate immune signaling pathways, as well as the relevant literature on the anti-CIRI effects of TCM through this mechanism, in order to provide a reference for the role and mechanism of TCM intervention in CIRI.