Finishing diets used in beef feedlots are high in energy to allow for rapid growth and fat deposition. Previous studies have shown that the use of high concentrate post-weaning diets changes expression of genes in the hypothalamus involved with regulating feed intake, metabolism, signaling, and neuronal communication. The objective of this study was to investigate whether expression of key growth and developmental genes in the hypothalamus can be altered by feeding a high concentrate diet when calves enter the feedlot. Predominantly Angus steers (n = 12) were randomly allocated to 1 of 2 treatment groups: (1) high energy/high concentrate (HE/HC), a diet fed to provide 1.33 mcal/kg NE gain; or (2) traditional backgrounding/finishing (B/F), fed to provide 1.10 mcal/kg NE gain for the first 84 d on feed (DOF) and 1.43 mcal/kg NE gain for the remaining 118 DOF. Growth at d28 (P < 0.01) was greater for the HE/HC treatment group; however, no difference between treatments was observed at the beginning (P > 0.14) and end (P > 0.13) of the feeding trial. At slaughter, hypothalami were dissected and frozen for RNA extraction. RNA was extracted and expression differences between treatments were measured by RNA-seq. Carcass characteristics and composition, and Warner-Bratzler shear force (WBSF) analysis were conducted. Kidney, pelvic, heart fat percentage was higher (P < 0.04) in HE/HC steers; however, no difference in other carcass traits (P > 0.10) and WBSF (P > 0.22) were detected. One hundred and 30 one genes were expressed only in the B/F steers, while 195 were only expressed in the HE/HC steers. Nine genes were expressed in both treatments; 3 genes had higher expression in the HE/HC steers and 6 genes had higher expression in B/F steers. Gene Ontology terms involved with differentially expressed genes included virus immune response, cell cycle regulation, signaling pathway regulation, and hydrogen and oxygen transport pathways. Feedlot calves fed a high concentrate diet upon entering the feedlot have altered gene expression in the hypothalamus, with many differentiated genes involved with signaling and metabolic pathways.