The regulatory effect of yak ghee sphingomyelin on lipid metabolism disorder and liver inflammation in high-fatdiet (HFD)-fed mice was investigated. Thirty C57 BL/6J male mice were randomly divided into five groups: low-fat control, high-fat, high-dose sphingomyelin (1.20 g/100 g ), medium-dose sphingomyelin (0.60 g/100 g) and low-dose sphingomyelin (0.30 g/100 g). Serum lipid levels were measured using commercially available kits, and the expression levels of lipid metabolism factors such as 3-hydroxy-3-methylglutarate coenzyme A reductase (HMGCR) and stearoyl-coenzyme A desaturase 1 (SCD1), and inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in liver tissues of each group were determined by enzyme-linked immunoassay (ELISA) and fluorescence quantitative polymerase chain reaction (PCR). The results showed that yak ghee sphingomyelin reduced serum total cholesterol, triglycerides and low-density lipoprotein cholesterol levels in HFD-fed mice (P < 0.05). The greatest decrease in the total cholesterol, triglycerides, low-density lipoprotein cholesterol and blood sugar levels was observed in the high-dose sphingomyelin group, by 26.26%, 24.70%, 38.96% and 42.16%, respectively. In addition, the expression levels of the HMGCR and SCD1 genes (P < 0.05) were significantly up-regulated and the pro-inflammatory cytokines TNF-α and IL-6 (P < 0.05) in liver tissue were down-regulated by sphingomyelin compared to the high-fat group. Consequently, yak ghee sphingomyelin can improve lipid metabolism disorders caused by HFD and prevent the occurrence of liver inflammation.