Purpose: Hypoxic-ischemic brain damage (HIBD) is one of the most common critical diseases in neonates and has high mortality and disability rates. Increasing evidence shows that long non-coding RNAs(lncRNA) plays an important role in the development of HIBD. Recently, acupuncture therapy has been found to be effective in the treatment of HIBD. However, the mechanism of lncRNA in acupuncture treatment of HIBD is still unclear. Method: In this study, a whole transcriptometric RNA-sequencing technique was applied to investigate transcriptome changes caused by acupuncture in PFC. Results: A total of 48 mRNAs (7 up-regulated and 41 down-regulated) and 65 lncRNAs (17 up-regulated and 48 down-regulated) was identified relate to acupuncture group and model group. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis, we found several lncRNAs and their target mRNAs were related to PI3K-Akt signaling pathway, TNF signaling pathway and NOD-like receptor signaling pathway, etc. Conclusion: we found several significant lncRNAs whose corresponding target genes might be the targets of acupuncture therapy for HIBD. The results of our study may provide new perspectives on the mechanism of acupuncture and affect the diagnosis and therapy of HIBD