Lysine addition to swine diets via either feed-grade lysine or protein sources costs producers. To better understand how diet affects lysine oxidation (LOX), weanling pigs were fed a control (C), high protein (HP), low protein (LP), high lysine (HL), or low lysine (LL) diets. No diet-induced alterations in lysine catabolism were detected in heart or kidney (P > 0.05). Liver lysine α-ketoglutarate reductase (LKR) (P < 0.05), saccharopine dehydrogenase (P < 0.05) activities, and α-aminoadipate δ-semialdehyde synthase abundance (P < 0.01) were reduced by 30%, 35%, and 52%, respectively, in pigs consuming LL compared with pigs consuming C. Expression of ornithine carrier-1 (ORC-1) mRNA in pigs fed HL was 170% greater (P < 0.05) than that in pigs fed C, whereas expression of the ORC-1 mRNA in pigs fed LL was 50% lower (P < 0.05) than that in pigs fed C. Expression of ORC-2 mRNA in pigs fed HL was 88% higher (P < 0.05) than that in pigs fed LL. The ORC transporters and LKR phosphorylation are likely points of regulation of LOX and, interventions aimed at these targets may be the best opportunity to decrease LOX and thus the requirement, subsequently decreasing feed costs.