Necrostatin-1 (Nec-1) has been shown to inhibit necroptosis and convey a significant protective effect after spinal cord injury (SCI). This small molecule inhibitor may reduce tissue damage and restore neurological function by lessening mitochondrial injury after SCI and preserving energy homeostasis. However, the effects of Nec-1 on endoplasmic reticulum stress (ERS)-an important pathological consequence of SCI-are still not clear. The present study investigates the relationship between necroptosis and ERS in a rat model of SCI. Electron microscopy was employed to observe ultra-structural changes in the endoplasmic reticulum and mitochondria after lesioning. Real-time quantitative PCR was used to measure the mRNA levels of ERS-related pro-apoptotic molecules such as C/EBP homologous protein (CHOP), immunoglobulin-binding protein (BiP/GRP78) and X box-binding protein-1 (XBP-1). Western blot and immunofluorescence were conducted to analyze CHOP, GRP78 and XBP-1 protein expression after lesioning. Results demonstrated that applying Nec-1 in SCI reduces ultra-structural damage to the endoplasmic reticulum and mitochondria and inhibits expression of ERS-related genes and proteins after lesioning. Immunofluorescence also shows ERS-related proteins mainly expressed in the cytoplasm of nerve cells. Taken together, these results demonstrate that Nec-1 has protective effect on the endoplasmic reticulum and mitochondria and alleviates ERS after SCI.