Nutritional alternatives to strengthen animal immunocompetence are critical for welfare and productivity in livestock systems, such as beef cattle operations. This experiment evaluated physiological and innate immunity effects of supplementing an immunomodulatory feed ingredient (Omnigen-AF; Phibro Animal Health, Teaneck, NJ, USA) to beef heifers administered bacterial lipopolysaccharide (LPS). In total, 8 non-pregnant, non-lactating nulliparous Angus×Hereford heifers (676±4 days of age) were ranked by BW (473±8 kg), and assigned to crossover design containing two periods of 34 days each. Heifers were housed in individual pens and had ad libitum access to meadow foxtail (Alopecurus pratensis L.) hay, water and a granulated commercial vitamin+mineral mix. Within each period, heifers received (as-fed basis) 227 g/day of dried distillers grains including (OMN) or not (CON) 56 g of Omnigen-AF for 34 days. On day 28 of each period (0800 h), heifers received an intravenous bolus dose (0.5 μg/kg of BW, diluted in 5 ml of 0.9% sterile saline) of bacterial LPS (Escherichia coli 0111:B4). Hay DM intake was recorded daily from day 0 to 34. Blood was collected at −1, 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 24, 48, 72, 96, 120 and 144 h relative to LPS administration. Heifer intravaginal temperature was recorded every 10 min from −0.5 to 10 h relative to LPS administration. No treatment effect was detected (P=0.35) for hay DM intake during the experiment. No treatment effects were detected (P⩾0.64) for intravaginal temperature and plasma concentrations of tumor necrosis-α, cortisol and haptoglobin, which increased (time effect, P<0.01) for OMN and CON heifers and peaked at 4.5, 2, 4 and 48 h, respectively, after LPS administration. No treatment effects were detected (P⩾0.35) for whole blood mRNA expression of chemokine ligand 5, tumor necrosis-α, cyclooxygenase 2 and interleukin 8, which also increased (time effect, P<0.01) for OMN and CON heifers and peaked at 0.5, 1.5, 2 and 2.5 h, respectively, after LPS administration. Whole blood mRNA expression of interleukin 8 receptor and L-selectin were also similar (P⩾0.61) between OMN and CON heifers, and decreased (time effect, P<0.01) for both treatments reaching nadir levels at 1 and 2.5 h, respectively, after LPS administration. Collectively, OMN supplementation did not modulate the physiological and innate immunity responses of beef heifers to bacterial LPS administration.