Both corn stover and rice straw as extensively available crop byproducts are rich in neutral detergent fiber and low in crude protein, which lead to lowered performance when they are fed to dairy cows. However, the metabolic mechanism behind is not clearly defined. This study was conducted to investigate the metabolic profiling and gene functions of liver using gas chromatography–time of flight/mass spectrometry based metabolomics and RNA-seq based transcriptomics when cows fed with rice straw (RS, n = 6) and corn stover (CS, n = 6), respectively. A total of 267 metabolites were measured in the liver. The principal component analysis (PCA), partial least squares discriminant analysis, and orthogonal partial least squares discriminant analysis showed that the metabolite profiles were separated based on diet. Among them, 24 significantly different metabolites (VIP > 1 and P < 0.05) were identified in the liver between CS and RS groups with 12 metabolites significantly higher and 12 metabolites significantly lower in the CS group. Pathway analysis based on significantly different metabolites revealed 5 key pathways (Impact value >0.5): linoleic acid metabolism, Gly, Ser and Thr metabolism, Phe, Tyr and Try biosynthesis, Ala, Asp and Glu metabolism, and Val, Leu, and Ile biosynthesis. In addition, 22 significantly different expressed genes (P < 0.0005, FDR <0.2) were identified in the liver between 2 groups. The molecular functions based on differential expressed genes indicated that the function of identical protein binding was upregulated in liver of the CS-fed cows (FDR = 0.0016) compared with those fed RS. Integrated analysis of metabolomics and transcriptomics revealed that Val, Leu, and Ile biosynthesis, and linoleic acid metabolism were the 2 top functional pathways that altered between CS and RS diets. Our results provide fundamental understanding on liver metabolic function and the mechanism behind which may provide information for future low quality forage utilization.