As an alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been increasingly used for fluoropolymer manufacture in recent years. Its growing detection in environmental matrices and wildlife raises considerable concern about its potential health risks. Here we investigated the effects of HFPO-TA on mouse liver following 28 days of exposure to 0.02, 0.1, or 0.5 mg/kg/d of HFPO-TA via oral gavage. Results showed that HFPO-TA concentrations increased to 1.14, 4.48, and 30.8 μg/mL in serum and 12.0, 32.2, and 100 μg/g in liver, respectively. Liver injury, including hepatomegaly, necrosis, and increase in alanine aminotransferase activity, was observed. Furthermore, total cholesterol and triglycerides decreased in the liver in a dose-dependent manner. Liver transcriptome analysis revealed that 281, 1001, and 2491 genes were differentially expressed (fold change ≥2 and FDR < 0.05) in the three treated groups, respectively, compared with the control group. KEGG enrichment analysis highlighted the PPAR and chemical carcinogenesis pathways in all three treatment groups. Protein levels of genes involved in carcinogenesis, such as AFP, p21, Sirt1 C-MYC, and PCNA, were significantly increased. Compared with previously published toxicological data of PFOA, HFPO-TA showed higher bioaccumulation potential and more serious hepatotoxicity. Taken together, HFPO-TA does not appear to be a safer alternative to PFOA.