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Feed efficiency (FE) is one of the most important economic traits in the porcine industry. In this study, high-throughput RNA sequencing (RNA-seq) was first utilized for brain tissue transcriptome analysis in pigs to indicate the potential genes and biological pathways related to FE in pigs. A total of 8 pigs with either extremely high-FE group (HE-group) or low-FE group (LE-group) were selected from 225 Duroc × (Landrace × Yorkshire) (DLY) pigs for transcriptomic analysis. RNA-seq analysis was performed to determine differentially expressed genes (DEGs) between the HE- and LE-group, and 430 DEGs were identified in brain tissues of pigs (|log 2 (FoldChange)| > 1; adjusted p -values <0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEGs were mainly enriched in synaptic signaling or transmission, and hormone secretion pathways, in which insulin secretion, and oxytocin signaling pathways were closely associated with FE by regulating feeding behavior and energy metabolism (adjusted p -values <0.05). Further, the transcription factors (TFs) analysis and gene co-expression network analysis indicated three hub differentially expressed TFs ( NR2F2 , TFAP2D , and HNF1B ) that affected FE by mainly regulating feeding behavior, insulin sensitivity, or energy metabolism. Our findings suggest several potential TFs and biological pathways for further investigations of FE in pigs.