We evaluated the plasma amine/phenol- and carbonyl-metabolome and whole-blood immune gene expression profiles in beef steers with divergent average daily gain. Forty-eight Angus crossbred beef steers (21 d post-weaning; 210 ± 8.5 kg of body weight) were fed the same total mixed ration ad libitum for 42 d with free access to water. After 42 d of feeding, the steers were divided into two groups of lowest (LF: n = 8) and highest average daily gain (HF: n = 8). Blood samples were taken from all steers. The blood samples from LF and HF steers were used for further analysis. A subsample of the whole blood was immediately transferred into ribonucleic acid (RNA)-protect tubes for RNA extraction and messenger RNA expressions of 84 genes involved in innate and adaptive immune responses. Another subsample of the whole blood was immediately centrifuged to harvest the plasma for subsequent metabolome analysis. The average daily dry matter intake of the steers in LF and HF were 6.08 kg ± 0.57 and 6.04 kg ± 0.42, respectively, and was similar between the two groups (P = 0.72). The average daily gain (1.09 kg ± 0.13) of LF was lower (P = 0.01) than that of HF (1.63 kg ± 0.20). The expressions of 10 immune-related genes were upregulated (FC ≥ 1.2; P ≤ 0.05) in HF steers; these genes were involved in viral pathogen recognition and eradication, defense against intracellular and extracellular pathogens and parasites, and immune response homeostasis. A total number of 42 carbonyl-containing metabolites and 229 amine/phenol-containing metabolites were identified in the plasma samples of both groups. No alteration in carbonyl-metabolome was detected. Ten metabolites with immunomodulatory, anti-inflammatory, and reactive oxygen-scavenging properties were greater (FDR ≤ 0.05) in HF steers, whereas 8 metabolites including arginine, phenylalanine, guanidoacetic acid, and aspartyl-threonine were greater in LF steers. This study demonstrated that beef steers with divergent average daily gain had altered plasma amine/phenol metabolome and immune-related gene expressions in the blood. Notably, plasma metabolites and immune-related genes of great health benefits were greater in steers with high average daily gain.