Astragalus membranaceus (Ast) and ligustrazine (Lig) have a protective effect on lower hemorrhagic transformation induced by pharmaceutical thrombolysis. The cerebral ischemia rat model was induced with autologous blood clot injections. A combination of Ast and Lig, or a protein kinase C delta (PKCδ) inhibitor-rottlerin, or a combination of Ast, Lig, and rottlerin was administered immediately after recombinant tissue plasminogen activator injection. The cerebral infarct area, neurological deficits, cerebral hemorrhage status, neuronal damage and tight junctions' changes in cerebral vessels, and the messenger RNA and protein levels of PKCδ, myristoylated alanine-rich C kinase substrate (Marcks), and matrix metallopeptidase 9 (MMP9) were determined after 3 h and 24 h of thrombolysis. The ultrastructure of the neuronal damage and tight junctions was examined under a transmission electron microscope. The expression levels of PKCδ, Marcks, and MMP9 were assessed by immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction . Administration of Ast and Lig not only significantly decreased neurological deficit scores, infarct volumes, and cerebral hemorrhage but also inhibited the disruption due to neuronal dysfunction and the tight junction integrity in the cerebral vessel. Treatment with a combination of Ast and Lig effectively protected ischemia-induced microhemorrhage transformation through PKCδ/Marcks pathway suppression.