This study aims to investigate the protective effects and underlying mechanisms of Salvia miltiorrhiza -Carthamus tinctorius drug pair (SCP) on isoprenaline hydrochloride (ISO)-induced myocardial ischemia in rats. An ISO-induced myocardial ischemia rat model was established to investigate myocardial infarction and related pathological changes. The myocardial infarction area and histopathological changes were assessed using 2,3,5-triphenyltetrazolium chloride staining and hematoxylin-eosin staining. Serum levels of myocardial enzymes, including aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), and cardiac troponin I (cTnI), were measured. Furthermore, the expression levels of extracellular matrix remodeling-associated proteins in myocardial tissue were analyzed using immunofluorescence and Western blot. These proteins included α-smooth muscle actin (α-SMA), phosphorylated nuclear factor-κB p65 (p-NF-κB p65), phosphorylated inhibitor of nuclear factor-κBα (p-IκBα), matrix metalloproteinase 9 (MMP9), endothelin-1 (ET-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-β1 (TGF-β1). The results indicated that SCP significantly reduced myocardial enzyme levels and infarct size in the model group, improved pathological changes, downregulated the expression of α-SMA, p-NF-κB p65, p-IκBα, MMP9, ET-1, and TGF-β1, and upregulated TIMP-1 expression (P<0.05). These findings suggested that SCP might protect against ISO-induced myocardial ischemia by modulating ECM remodeling-associated proteins.