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<b>Background</b>: Increasing attention has been given to the search for neuroprotective ingredients from natural plants. <i>Myrica rubra</i> bark (MRB) has been used in traditional oriental medicine for over thousand years and has potential neuroprotection. <b>Methods and Results</b>: Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was used to identify the compounds in MRB extract, and the MTT assay was performed to evaluate the neuroprotection of six major compounds from MRB against glutamate-induced damage in PC12 cells. The result displayed nineteen compounds were identified, and myricitrin and myricanol 11-sulfate were shown to have neuroprotection, which prevented cell apoptosis through alleviating oxidative stress by reducing the levels of reactive oxygen species and methane dicarboxylic aldehyde, as well as by enhancing the activities of superoxide dismutase. <b>Conclusions</b>: Several active compounds from MRB may offer neuroprotection and have the potential for the development of new drugs against central nervous system diseases.