Several phenylethanoid glycoside derivatives were designed and synthesized. Most of the synthetic compounds showed significant neuroprotective effects, including antioxidative and anti-apoptotic properties. Specifically, target compounds displayed potent effects against various toxicities such as H2O2 and 6-hydroxydopamine (6-OHDA) in PC12 cells. Among the synthetic derivatives, three compounds (5, 6, 8) exhibited much superior activities to the marketed drug Edaravone. The compounds were able to prevent the 6-OHDA-induced damage in PC12 cells in a dose-dependent manner. The anti-apoptotic effects could be observed via cell morphological changes. Moreover, the compounds significantly reduced the intracellular ROS increase resulting from 6-OHDA treatment. The preliminary structure-activity relationships were also explored. Compounds 5, 6, 8 may hold the potential as promising neuroprotective agents and new lead compounds for the treatment of neurodegenerative diseases or cerebral ischemia.