Stroke is the leading cause of death and disability worldwide, and ischemic stroke accounts for more than 85% of the stroke incidence. Tissue plasminogen activator (t-PA) is the only FDA-approved drug for ischemic stroke treatment with a narrow treatment time window of 4.5 h. Hemorrhagic transformation (HT) is a severe complication of delayed t-PA treatment in ischemic stroke. Thus, it is critically important to develop combination therapies to reduce HT and extend the therapeutic time window of t-PA. Current progress suggests that peroxynitrite (ONOO -)/high-mobility group box 1 protein (HMGB1)/matrix metalloproteinase-9 (MMP-9) signaling cascades could be important for attenuating HT during thrombolytic treatment for acute ischemic stroke. Recently, important progress has been made in seeking for natural compounds from Chinese medicine for reducing ischemic stroke injury, with some of them targeting ONOO -/HMGB1/MMP-9 signaling cascades. Herein, we analyze the roles and interactions of these three targets in mediating HT; subsequently, we summarize the potential compounds from Chinese herbal medicine for attenuating HT and analyze the related targets. Finally, we raise the potential issues to be addressed in further development of these compounds as combination therapy.