Oxidative stress is a major pathogenic event associated with almost all the clinical and experimental conditions of chronic liver disorders, ranging from hepatitis to cancer. The use of antioxidants, including vitamin C, has therefore been widely applied as therapeutic agents. However, little is known about molecular mechanisms for their roles in liver health. The aim of this study was to identify vitamin C responsive genes for optimal liver health using a mouse model of scurvy, sfx mice, which display fracture-dominant phenotypes due to Gulo mutation. We conducted vitamin C rescue treatment in 3 female sfx mice and compared their hepatic gene expression profiling with that of wild-type mice using Illumina Mouse-6 Expression BeadChips together with functional clustering using bioinformatics DAVID tools. Hepatic vitamin C concentration was also assayed and compared. Our results showed that 269 transcripts were differentially expressed greater than or equal to twofold between these two groups of mice. Remarkably, five liver-specific genes, including Ass1, Cth, Cfhl1, F8, and Cyp3a41 were found to be upregulated in the rescued mice. These genes are involved in liver damage, regulation of cell proliferation, coagulation, infection, or drug and steroid metabolism. Since vitamin C concentration in rescured mice was significantly lower than wild-type mice, these changes may represent the effects of suboptimal vitamin C content on liver health in mice. Moreover, a battery of responsive target genes involved in MAPK signaling regulation was identified. It is concluded that supplementary antioxidant vitamin C intake is beneficial for optimal liver health through involvement in the regulation of multiple molecular events, especially those associated with cell proliferation, signal transduction, biosynthesis and antitoxification.