Oxidative stress is detrimental to animals. Previous studies have indicated that arginine (Arg) may function as a potential substance against oxidative stress. The present study was conducted to explore the potential mechanisms behind the Arg-induced protective effects against oxidative stress in piglets. A total of thirty-six piglets were randomly allocated to six groups with six replicates per group. Piglets were subjected to three dietary treatments (namely two groups per treatment) in week 1 and fed with a basal diet (ArgL) or the basal diet supplemented with 0.8% (ArgM) or 1.6% (ArgH) L-Arg, respectively. On day 8, piglets were injected intraperitoneally either with diquat (10 mg/kg body weight) or sterile saline. The whole trial lasted 11 d. Results showed that dietary Arg supplementation did not affect growth performance in week 1. Oxidative stress significantly decreased the growth performance of piglets (P < 0.05). However, ArgH attenuated the negative effects of oxidative stress on feed intake and significantly increased the total antioxidant capacity in the liver under oxidative stress (P < 0.05). Both ArgM and ArgH enhanced the activities of plasma glutathione peroxidases and superoxide dismutases and decreased the IL-6 and TNF-a mRNA level in the liver under oxidative stress (P < 0.05). The present study not only shows that Arg can function as a potential nutrient to alleviate oxidative stress responses through the enhancement of antioxidant capacity, and inhibition of the expression of inflammatory cytokines, but the results also suggest that alleviation of oxidative stress responses using dietary nutrient components deserves further attention in the future.