Previous studies in dairy cattle fed OmniGen-AF (OG, Phibro Animal Health, Teaneck, NJ) show OG modulates innate immunity and blood metabolites after 45 to 60 d with continuous feeding. Interestingly, in beef cattle a shorter interval between measured changes in immune signaling following the onset of OG feeding have been observed. However, this work has been limited to identifying cellular signals in healthy, unchallenged beef heifers. This study aimed to investigate immune and metabolic responses in beef and dairy heifers challenged with LPS after 28 d of feeding OG. Angus (n = 14) and Holstein (n = 15) heifers were assigned based on BW (within breed) to 2 dietary treatments: TMR top dressed with OG (OG, 4g/45.36 kg BW, beef n = 7, dairy = 8) or placebo (CON, 4g/45.36 kg BW beef n = 7, dairy n = 7). All heifers were fed their respective diets continuously and on d 28 were challenged with an IV LPS bolus (0.125 µg/kg BW). Complete blood counts and serum metabolites, were analyzed at different hours relative to LPS bolus (hour), period during which heifers were still on their respective dietary treatments. Data were analyzed using the PROC Mixed procedure of SAS with hour, treatment, breed, and all interactions evaluated as fixed effects. Treatment interactions with hour were not significant (P > 0.05). No differences in neutrophil counts, serum cortisol, or serum insulin were detected between treatments or its interaction with breed (P > 0.05). Heifers fed OG had increased monocyte counts and greater neutrophil:lymphocyte ratio compared with CON (P < 0.01). In beef heifers, OG reduced lymphocyte counts and serum NEFA but increased eosinophil counts and serum glucose compared with CON (treatment × breed interaction, P < 0.01). In dairy heifers, OG increased RBC counts compared with CON (treatment × breed interaction, P = 0.03). In conclusion, continuously feeding OG for 28 d altered blood cell populations and metabolism in beef and dairy heifers in response to LPS although beef heifers were more metabolically responsive. These data suggest cattle fed OG for as short as 28 d may be better suited to cope with stressors.