The present study aimed to investigate the role of microRNA (miR)-219-5p in spinal cord injury (SCI) and to examine the underlying molecular mechanism. SCI rat and cell models were conducted in the current study， while reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the level of miR-219-5p in the SCI mice and neurons. Bioinformatics analysis was applied to predict the target genes of miR-219-5p， and dual-luciferase reporter assay was performed to verify the prediction. In addition， MTT assay and flow cytometry were conducted to determine the cell viability and cell apoptosis of the neurons， respectively. Western blot analysis was also performed to detect the expression of associated proteins. The study results demonstrated that miR-219-5p was highly expressed in SCI mice and neurons， and directly targets liver receptor homolog-1 (LRH-1). The neuron viability was significantly reduced by SCI， however， it was recovered upon transfection with an miR-219-5p inhibitor. Neuron apoptosis was notably induced by SCI and inhibited by miR-219-5p inhibition. The LRH-1/Wnt/β-catenin signaling pathway was also inhibited by SCI， while it was significantly enhanced by the miR-219-5p inhibitor. Furthermore， LRH-1 overexpression eliminated the effects of the miR-219-5p inhibitor on SCI. In conclusion， these data indicated that the miR-219-5p inhibitor served a protective role in SCI via regulating the LRH-1/Wnt/β-catenin signaling pathway.