4-Acylated or 3,4-diacylated caffeic acid phenethyl ester (CAPE) was prepared as prodrug to improve its stability and lipid solubility. Their neuroprotective activities were assessed by H202 model and 6-OHDA model. The results showed that target compounds displayed positive abilities to protect PC 12 nerve cells from oxidative stress injury, superior to that of CAPE. Additionally, target compounds showed high blood-brain barrier permeability.