Abstract: In traditional Chinese medicine, Ligusticum wallichii (Chuan Xiong) and its bioactive ingredient, tetramethylpyrazine (TMP), have been used to treat cardiovascular diseases. This work investigated whether ultrasound (US) exposure could enhance the protective effect of TMP against cerebral ischemia/reperfusion (I/R) injury. Glutamateinduced toxicity to pheochromocytoma (PC12) cells was used to model I/R injury. TMP was paired with US to examine whether this combination could alleviate glutamate induced cytotoxicity. The administration of TMP effectively protected cells against glutamate-induced apoptosis, which could be further enhanced by US-mediated sonoporation. The anti-apoptotic effect of TMP was associated with the inhibition of oxidative stress and a change in the levels of apoptosisrelated proteins, Bcl-2 and Bax. Furthermore, TMP reduced the expression of pro-inflammatory cytokines such as TNF-α and IL-8, which likely also contributes to its cytoprotective effects. This work suggests that ultrasound-enhanced TMP treatment might be a promising therapeutic strategy for ischemic stroke.