Swertiamarin (STM) is a natural compound from Swertia mussotii Franch. (Gentianaceae) that exhibits various pharmacological effects. The current study tested the potential neuroprotective activity of STM in human neuroblastoma SH-SY5Y cells challenged with oxygen-glucose deprivation/reoxygenation (OGDR). Cell Counting Kit-8 assays were used to assess cell viability and the JC-1 assay were performed to evaluate changes in mitochondrial membrane potential (ΔΨm). The intracellular levels of ROS production were measured by 20,70-dichlorofuorescein diacetate (DCFH-DA) staining and flow cytometry. In addition, neuronal apoptosis was evaluated by staining with annexin V and flow cytometry. The determinations had also been made on TLR4-related proteins by Western blot analysis. Results show that exposure to OGDR significantly decreased cell viability but this decrease was attenuated by pretreatment with STM. STM also significantly attenuated declines in ΔΨm, inhibited OGDR-induced increases in intracellular ROS production, and reduced cell apoptosis. OGDR notably induced TLR4, Myd88, NF-κB p65 and PARP1 expression levels in the cells. However, treatment with STM reduced the expression of TLR4, Myd88, NF-κB p65 and PARP1. In conclusion, STM protected SH-SY5Y cells against OGDR-induced injury by attenuating increases in ROS levels and suppressing apoptosis, at least in part, via TLR4/PARP1/NF-κB pathway.