The objective of this study was to evaluate the effect of a postbiotic additive from Aspergillus oryzae (AO) on the inflammation response in lactating dairy cows exposed to heat stress. Thirty-six Holstein cows (105 ± 23 SD days in milk, 714 ± 23 kg body weight) were used in a completely randomized design and randomly assigned to 1 of 3 treatments for 36 d: 0 g/d (control; CTL), 3 g/d (low), and 6 g/d (medium) of the AO postbiotic (Biozyme Inc., St. Joseph, MO). A 41% forage and 59% concentrate TMR (18.1% CP, 33.0% NDF, 1.61 Mcal/kg NEL) was individually fed twice daily, and AO was top-dressed twice daily. Cows experienced warm climate during June and July 2018. Cows were provided with heat abatement of fans and misters from d 1 to 10 (period 1) and without heat abatement from d 11 to 36 (period 2). Acute phase proteins [haptoglobin, serum amyloid A, and lipopolysaccharide (LPS) binding protein] were determined from plasma collected on d 11 and 35. On d 36, 2 whole blood samples were collected for an ex-vivo challenge with or without LPS (5 μg/μL). The expression of IL-1β, IL-6, and TNF-α was measured using qPCR. Three analyses were conducted on cytokine expression: 1) no LPS stimulation, 2) LPS stimulation, and 3) ratio of LPS to no LPS stimulation. Mild heat stress was attained in period 1, whereas heat stress intensity was increased in period 2 (temperature-humidity index = 74.6 ± 2.4 and 77.3 ± 4.2 [mean ± SD]). In period 1, AO quadratically decreased (P = 0.03) LPS binding protein concentrations in plasma by 25.7%. In period 2, AO quadratically decreased (P = 0.01) serum amyloid A concentrations in plasma by 65.6% and tended to quadratically decrease (P ≤ 0.10) haptoglobin and LPS binding protein concentrations by 35.4 and 23.3%, respectively. From the ex vivo LPS challenge, AO linearly decreased (P = 0.02) the IL-6 expression ratio (LPS to no LPS stimulation) by 65.6%. In summary, AO decreased markers of inflammation and cytokine production in cows exposed to heat stress. These findings may be associated with improvements of health in cows exposed to heat-stress.