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Simple Summary: Yaks are a major economic source for people in the Tibetan Plateau region. Yaks are rich in nutrients, but their low fat content is not conducive to the large-scale promotion of yak meat, so the study of the mechanism of yak lipid deposition is beneficial to the marketing of yak meat. In this paper, the results of transcriptome sequencing analysis of yak liver showed that it could be determined that the expression levels of genes associated with partial lipid deposition were significantly up-regulated during yak fattening. In addition, this study found that the tenderness of yak meat improved during this process. Fattening significantly affects fat deposition in yaks, which may be realized through its effects on lipid metabolic pathways. Therefore, studying the mechanism of lipid deposition in yaks and fattening yaks will improve the quality of yak meat. Yak meat is nutritionally superior to beef cattle but has a low fat content and is slow-growing. The liver plays a crucial role in lipid metabolism, and in order to determine whether different feeding modes affect lipid metabolism in yaks and how it is regulated, we employed RNA sequencing (RNA-seq) technology to analyze the genome-wide differential gene expression in the liver of yaks maintained under different raising systems. A total of 1663 differentially expressed genes (DEGs) were identified (|log2FC| ≥ 0 and p-value ≤ 0.05), including 698 down-regulated and 965 up-regulated genes. According to gene ontology (GO) and KEGG enrichment analyses, these DEGs were significantly enriched in 13 GO terms and 26 pathways (p < 0.05). Some DEGs were enriched in fatty acid degradation, PPAR, PI3K-Akt, and ECM receptor pathways, which are associated with lipid metabolism. A total of 16 genes are well known to be related to lipid metabolism (e.g., APOA1, FABP1, EHHADH, FADS2, SLC27A5, ACADM, CPT1B, ACOX2, HMGCS2, PLIN5, ACAA1, IGF1, FGFR4, ALDH9A1, ECHS1, LAMA2). A total of 11 of the above genes were significantly enriched in the PPAR signaling pathway. The reliability of the transcriptomic data was verified using qRT-PCR. Our findings provide new insights into the mechanisms regulating yak meat quality. It shows that fattening improves the expression of genes that regulate lipid deposition in yaks and enhances meat quality. This finding will contribute to a better understanding of the various factors that determine yak meat quality and help develop strategies to improve yield and quality. [ABSTRACT FROM AUTHOR]