Objective To investigate the difference in tissue distribution of ligustrazine hydrochloride and Salvia miltiorrhiza (Danshen) in acute myocardial ischemia (AMI) model rats. Methods A rat model of AMI was induced by subcutaneous injection of isoproterenol hydrochloride solution. The rats were then divided into a ligustrazine group, Danshen group, and ligustrazine-Danshen group. Ligustrazine and Danshensu levels in the heart, liver, spleen, lung, kidney, and brain were detected at different time points by ultra-high performance liquid chromatography/ tandem mass spectrometry. Results Ligustrazine and Danshensu were widely distributed and peaked rapidly in tissues of AMI rats after intravenous injection. Before and after compatibility, the content of ligustrazine was highest in brain tissue and lowest in liver tissue, while the Danshensu content was highest in kidney tissue and lowest in brain tissue, indicating that ligustrazine could penetrate the blood-brain barrier more easily than Danshensu, and the main sites of accumulation were different. The areas under the curves of ligustrazine and Danshensu in the heart as the target organ were significantly increased (P<0. 001). Conclusions These result suggest that the combination of ligustrazine and Danshen may enhance the therapeutic effect by increasing the distribution of the main pharmacodynamic components in the heart, thus improving the efficacy.