This study was conducted to investigate the effects of pyrroloquinoline quinone disodium (PQQ.Na-2) on inflammatory responses, oxidative stress, and intestinal morphology of broiler chickens challenged with lipopolysaccharide (LPS). A 2 x 2 factorial arrangement in a complete randomized design experiment was used to study the effect of dietary PQQ.Na-2 (0 or 1 mg/kg) on broiler chickens with or without a challenge with LPS. A total of two hundred eighty-eight 1-day-old Arbor Acre broiler chickens were randomly assigned to 4 treatments with 6 replicate cages of 12 birds per cage. All experimental broilers were injected intraperitoneally with 0.5 mg/kg body weight of either Escherichia coli LPS or sterile saline at 16, 18, and 20 d of age. Results showed that injecting LPS significantly increased the concentrations of interleukin-1beta (IL-1 beta) in serum of birds on day 20 and day 21. Meanwhile, LPS injection increased (P < 0.05) the relative mRNA expression of interleukin-6 (IL-6) in the duodenal mucosa of broilers on day 21. However, dietary supplementation with PQQ.Na-2 decreased (P < 0.05) the concentration of IL-6 in serum of birds on day 20 and the levels of IL-1 beta, IL-6, and interleukin-10 (IL-10) in serum of broiler chickens on day 21. Besides, supplementation of PQQ.Na-2 within diet decreased (P < 0.05) the mRNA expressions of IL-1 beta and IL-10 in the duodenal mucosa of birds on day 20. Relative to saline injection, the activity of glutathione peroxidase (GSH-Px) in serum and the activities of total superoxide dismutase (T-SOD) and catalase (CAT) in liver were found to be lower (P < 0.05) in broilers after LPS challenge on day 21. However, birds fed with PQQ.Na-2 showed higher (P < 0.05) GSH-Px activity in serum and higher (P < 0.05) T-SOD activities in liver on day 21 and day 42. Pyrroloquinoline quinone disodium also significantly attenuated the LPS-induced decreases in villus height to crypt depth ratio in the duodenum of broilers. In conclusion, dietary PQQ.Na-2 supplementation significantly exerted protective effects on inflammation damage and oxidant stress of broilers under LPS challenge by regulating the expression of inflammatory cytokines (IL-1 beta, IL-6, and IL-10) and activities of antioxidant enzymes (GSH-Px, T-SOD, and CAT). Moreover, dietary PQQ.Na-2 supplementation significantly ameliorated the LPS-impaired intestinal morphology in broilers. Therefore, it has been considered that PQQ.Na-2 can be used as a potential feed additive in broiler production.