The herb Cistanche deserticola has some myocardial protective effects. This study attempted to explain the mechanism by which PhG-RE protects myocardial cells and verify if this protection occurs through regulating the apoptosis mechanism associated with endoplasmic reticulum stress (ERS). Rat myocardial cells were exposed to 150 μg·mL−1 PhG-RE for 24 h and then to 100 μmol·mL−1 H2O2 for 18 h to induce ERS and establish a cell damage model. Thapsigargin (TG), a specific ERS activator, and 4-phenylbutyric acid (4-PBA), an ERS inhibitor, were used to validate the accuracy of the experiment. Our results demonstrated that PhG-RE significantly improved cell viability, protected cells, and reduced cell damage and apoptosis. PhG-RE played a role similar to that of the ERS inhibitor 4-PBA in protecting myocardial cells against apoptosis and damage induced by ER stress. Furthermore, PhG-RE significantly attenuated the mRNA expression of the ERS-associated apoptotic factors GRP78, CHOP, and Caspase-12 and the protein expression of the ERS-associated apoptotic factors GRP78, CHOP, Caspase-12, and p-JNK. Taken together, these findings suggest that PhG-RE can effectively protect myocardial cells and reduce cell apoptosis and damage, which may be related to the regulation of ERS-associated apoptosis.