Objectives of this research were to examine differential gene expression profiles of Nguni and Bonsmara cattle fed diets differing in their energy density. The ultimate goal was to improve understanding of the mechanisms that underlie differences between these breeds and the potential interactions of the differences between breeds with the nutritive environment. The experiment was designed as a 2 × 2 factorial arrangement of breed and diet (12.5 MJ/kg DM vs. 10.9 MJ/kg DM). The initial feeding trial had 10 bull calves per treatment. However, financial constraints limited RNA sequencing to six animals per treatment and the RNA generated from one animal was of insufficient quality to be useful. Transcripts with false discovery rate P-values <0.05 and fold-changes >2.0 were considered significant. Bonsmara had a faster growth rate, heavier live and carcass weights, and better feed conversion compared to Nguni. However, lower levels of fat were observed in Nguni. Twenty different genes were differentially expressed, with three exhibiting interaction effects and all 20 having differences in transcript abundance between the breeds. A dietary effect was only observed for the one gene and that gene was also subject to an interaction effect with breed. Observed differences in gene expression between Bonsmara and Nguni by several genes affecting the structure or function of the mitochondria imply differences in energy metabolism between the breeds. Interaction effects on the abundance of some gene transcripts indicate the need to consider the diet when evaluating breed differences and conversely, consider breed when evaluating diets.