This study was aimed at investigating the differentially expressions of long noncoding RNAs (lncRNAs) and mRNAs in the brains of a middle cerebral artery occlusion/reperfusion (MCAO/R) group and a MCAO/R + 20(R)-Rg3 group. Biological enrichment analysis was performed, and a lncRNA-mRNA coexpression network was constructed, to reveal the targets and pathways of 20(R)-Rg3 involved in the regulation of cerebral ischemia-reperfusion injury (CIRI). The RNA-seq high-throughput sequencing method was employed to detect differentially-expressed genes between the groups, which were verified by RT-PCR. Functional enrichment analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed to explore the biological functions and relevant pathways. The coexpression network of the screened lncRNAs and mRNAs was built by using Cytoscape software. The results identified 77 upregulated lncRNAs, 162 downregulated lncRNAs, 66 upregulated mRNAs and 472 downregulated mRNAs in the MCAO/R + 20(R)-Rg3 group, compared with those in the MCAO/R group. GO enrichment analysis showed that the GO terms were mainly enriched in stimulation response, cellular response, and stress response. KEGG pathways were mainly related to the tumor necrosis factor (TNF), NF-\kappaB, cytokine, and other receptor signaling pathways. In addition, the coexpression analysis between lncRNA and mRNA identified 314 nodes and 515 connections between 6 lncRNAs and 308 mRNAs, of which 511 were positive and 4 were negative. Among them, ENSRNOG-00000059555 was strongly correlated with AABR07001160.1. This study revealed multiple lncRNAs were involved in the neuroprotection of 20(R)-Rg3 against CIRI and thereby provided new insights into the use of 20(R)-Rg3 as a novel neuro protectant in ischemic stroke management.