Cerebral ischemia threatens human health and life. Hyperlipidemia is a risk of cerebral ischemia. Danhong injection (DHI) is a traditional Chinese medical preparation for the treatment of cerebrovascular diseases. However, the effects of DHI on mitochondria-dependent apoptosis and mitochondrial function following cerebral ischemia in hyperlipidemia rats are not clear. In this study, SD rats were fed by high-fat diet for six weeks to establish the hyperlipidemia model, except for the sham and ischemia-reperfusion (I/R) groups. Hyperlipidemia rats were assigned into I/R + high-fat diet (HFD) group, DHI 1 mL/kg group, and DHI 2 mL/kg group. DHI was administrated to the drug group via caudal vein for seven consecutive days (once per day). Subsequently, rats underwent middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. The results showed that DHI significantly reduced cerebral infarction volume, ameliorated neurological function, improved pathological changes, and inhibited apoptosis. DHI could significantly restore the levels of mitochondrial respiratory chain complexes I-IV, increase the ATP content and COX activity, and decrease the level of OFR in the ischemic brain mitochondria of hyperlipidemia rats after I/R. DHI significantly regulated the levels of cytochrome c (Cyt c), Apaf1, Bax, Bcl-2, Caspase-3, and Caspase-9 in brain tissue, and improved mitochondrial dynamics (Mfn1, Mfn2, OPA1, Drp1, and Fis1). The results indicate that DHI could alleviate ischemic brain injury in hyperlipidemia rats, and the mechanism may be to improve mitochondrial function by restoring the mitochondrial respiratory chain and changing the protein balance of mitochondrial fusion and fission, and inhibiting mitochondria-dependent apoptosis.