Qilian sheep are an important local breed of Tibetan sheep with strong adaptation to cold and hypoxic environments. To identify candidate genes related to nutrient metabolism in Qilian sheep, this study compared liver transcriptomes between Qilian sheep and Oula sheep raised under the same grazing and feeding conditions. Six 10-month-old ewes were selected from each breed, and three liver samples with high RNA quality from each group were used for transcriptome sequencing. Differential expression analysis identified 1640 differentially expressed genes under the thresholds of |log2FoldChange| > 1 and false discovery rate < 0.05, including 718 upregulated and 922 downregulated genes. KEGG enrichment analysis showed that these genes were mainly involved in lipid metabolism- and amino acid metabolism-related pathways, especially the peroxisome proliferator-activated receptor signaling pathway, fatty acid synthesis, and fatty acid beta-oxidation. qRT-PCR validation confirmed that RGN, LPGAT1, and BHMT2 were significantly upregulated, whereas SDS, GK, PC, MIOX, HMGCS2, PNPLA3, ACAA2, and HADHA were downregulated in Qilian sheep. These results indicate clear differences in liver nutrient metabolism-related gene expression between Qilian sheep and Oula sheep and provide a molecular basis for understanding the liver metabolic characteristics and adaptive metabolic mechanisms of Qilian sheep.