Feed efficiency (FE) is an important trait in the porcine industry. Therefore, understanding the molecular mechanisms of FE is vital for the improvement of this trait. In this study, 6 extreme high-FE and 6 low-FE pigs were selected from 225 Duroc × (Landrace × Yorkshire) (DLY) pigs for transcriptomic analysis. RNA-seq analysis was performed to determine differentially expressed genes (DEGs) in the liver tissues of the 12 individuals, and 507 DEGs were identified between high-FE pigs (HE- group) and low-FE pigs (LE- group). A gene ontology (GO) enrichment and pathway enrichment analysis were performed and revealed that glycolytic metabolism and lipid synthesis-related pathways were significantly enriched within DEGs; all of these DEGs were downregulated in the HE- group. Moreover, Weighted gene co-expression analysis (WGCNA) revealed that oxidative phosphorylation, thermogenesis, and energy metabolism-related pathways were negatively related to HE- group, which might result in lower energy consumption in higher efficiency pigs. These results implied that the higher FE in the HE- group may be attributed to a lower glycolytic, energy consumption and lipid synthesizing potential in the liver. Furthermore, our findings suggested that the inhibition of lipid synthesis and glucose metabolic activity in the liver may be strategies for improving the FE of DLY pigs.