Objective Transcriptome sequencing technology (RNA-seq) was used to analyze the mechanism of compound Dancao granules as an intervention for high-fat feed combined with carbon tetrachloride (CCl₄ )-induced nonalcoholic steatohepatitis. Methods 45 male C57BL/6J mice were split into two groups at random: normal control group, model control group, obeccholic acid group 10 mg/(kg·d), and compound Dancao granules low- and high-dose groups 3.74g/(kg·d) and 7.48g/(kg·d), with 9 mice in each group. Normal diet was made available to the control group,and the mice in the model group were given a high-fat diet combined with the subcutaneous injection of CC1₄ , with 100% CC1₄ solution (4 mL/kg) in the first application, and 40% CC1₄-olive oil solution (2 mL/kg) in the second application, twice a week for a total of 6 weeks. Each drug group was administered the respective drug from week 3 for a total of 4 weeks. 12 h after the last administration, the serum and liver tissues of mice in each group were collected, and a biochemical kit was used to detect serum liver function. Hematoxylin-eosin (HE), sirius scarlet, and oil red O staining were used to examine histopathological changes to the liver. The levels of IL-6, IL-10, TNF-α and TGF-β in mice liver were detected via ELISA, and the expression of α-SMA was observed by immunohistochemistry. Differential gene expression was analyzed by RNA-seq and functional enrichment analysis. To verify the differential expression of mRNA, quantitative reverse transcription PCR(qRT-PCR) was used. TDT-mediated dUTP nick-end labeling (TUNEL) staining was employed to identify apoptosis. Results The model control groups had significantly higher levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and triglycerides (TG) than normal control group (P<0.01). Additionally, there was obvious inflammatory cell infiltration in the liver tissue, collagen deposition in the sink and interlobule areas, and a significant increase in lipid droplet area (P<0.01). The levels of IL-6 and TNF-α in liver tissue were significantly increased (P<0.01), the levels of IL-10 and TGF-β were decreased (P<0.01), and the expression of α-SMA was significantly increased (P<0.01). The levels of TC, TG, ALT, and AST were significantly lower in groups that received compound Dancao granules and obeccholic acid than the model control group (P<0.01), and inflammatory cell infiltration, collagen deposition, and fat accumulation in the sink and interlobule areas were improved (P<0.01). The levels of IL-6 and TNF-α in liver tissue were significantly decreased (P<0.01), the levels of IL-10 and TGF-β were increased (P<0.05, P<0.01), and the expression of α-SMA was significantly decreased (P<0.01). RNA-seq sequencing result showed that 2819 genes in the normal control group were differentially expressed compared with the model control group, with 543 up-regulated and 2276 down-regulated genes. In a comparison of the model control group and compound Dancao granules group, 240 genes were differentially expressed, including 206 upregulated genes and 34 down-regulated genes. There were 221 genes with overlapping expression in the 2 groups and functional enrichment highlighted cell cycle(Cdt1, Plk1, Bub1b, Ttk, Knl1, Esco2, Cdc6, Ndc80, Cdc25b, Sgo1, Ccnb2, Espl1, Ccne1, Mcm4, Mcm5, Fbxo5, Bub1, Mcm2), apoptosis(Caspase3, Bax, P53, Apaf1, Bak, Caspase8), the P53 signaling pathway (P53, Ccnb2, Apaf1, Bak, Bax, Gtse1, Caspase3, Ccne1), arachidonic acid metabolism (Hpgds, Cyp2c54, Cyp2b10, Tbxas1, Cyp2c50), galactose metabolism (Hk3, Gla, Hk2, Akr1b7) and other signaling pathway genes. RNA-seq sequencing analysis showed that compound Danicao granules mainly regulated the apoptosis signaling pathway, and qRT-PCR confirmed that the mRNA expression of Caspase3, Bax, P53, Apaf1, Bak and Caspase8 in the liver tissue of the model control group was increased compared with that of the normal control group (P<0.01). Compared with the model control group, the compound Dancao granules group showed decreased mRNA expression of Caspase3, Bax, P53, Apaf1, Bak and Caspase8 in liver tissue (P<0.01). TUNEL staining showed that the number of cells showing nuclear shrinkage and apoptotic bodies decreased in the compound Dancao granule administration group. Conclusions Compound Dancao granules had a significant protective effect against non-alcoholic steatohepatitis induced by high-fat feed combined with CCl₄ , and its mechanism might be connected to the control of genes linked to apoptosis.