Tibetan sheep have lived on the Qinghai-Tibetan Plateau for thousands of years and they have a good adaptability to the hypoxic environment and strong disease resistance. However, the molecular mechanism of the Tibetan sheep adapting to this extreme environment, especially the role of genetic regulation is still unknown. Emerging evidence suggests that long non-coding RNAs (lncRNAs) participate in the regulation of a diverse range of biological processes. To explore the potential lncRNAs involved in Tibetan sheep adapting to high altitude hypoxia environment, we analyzed the expression profile of lncRNAs and mRNAs in liver and lung tissue of sheep based on the comparative transcriptome analysis between four Tibetan sheep populations (high altitude) and Hu sheep (low altitude). The results showed a total of 7848 differentially expressed (DE) lncRNAs transcripts and 22971 DE mRNAs transcripts were detected by pairwise comparison. The expression patterns of selected mRNAs and lncRNAs were validated by qRT-PCR and the results correlated well with the transcriptome data. Moreover, the functional annotation analysis based on the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases showed that DE mRNAs and the target genes of the lncRNAs were significantly enriched in organ morphogenesis, response to stimulus, heme binding, immune system, arginine and proline metabolism, and fatty acid biosynthesis. The prediction of mRNA-mRNA and lncRNA-mRNA interaction networks further revealed transcripts potentially involved in adaptation to high altitude hypoxia, the hub genes that DDX24, PDCD11, EIF4A3, NDUFA11, SART1, PRPF8 and TCONS_00306477, TCONS_00306029, TCONS_00139593, TCONS_00293272, TCONS_00313398 were selected. Additionally, a set of target genes, PIK3R1, IGF1R, FZD6, IFNB2, ATF3, MB, CYP2B4, PSMD13, and TGFB1 were also identified as candidate genes associated with high altitude hypoxia adaptation. In conclusion, a collection of aberrantly expressed lncRNA, a set of target genes and biological pathways known to be relevant for altitude adaptation were identified by comparative transcriptome analysis between Tibetan sheep and Hu sheep. Our results first identified the characterization and expression profile of lncRNAs between Tibetan sheep and Hu sheep and provides insights into the genetic regulation mechanisms for Tibetan sheep adaptation to high altitude hypoxia environments.