Indole-3-propionic acid (IPA) has anti-inflammatory properties, which can be beneficial for weaned piglets with underdeveloped immune systems. The study explores the impact of IPA supplementation on growth performance, oxidative stress, and inflammation response in weaned piglets. In experiment (Exp.) 1, ninety weaned piglets were divided into six groups (five replicates per group, three pigs per replicate), with each group receiving a basal diet with varying amounts of IPA (0, 50, 100, 200, 400, or 600 mg/kg) for 42 d. Piglets fed the diets with 50, 100, and 200 mg/kg of IPA exhibited reduced feed conversion ratios (F: G) compared to the control piglets (P = 0.035). Notably, 50 and 100 mg/kg IPA treatments significantly reduced diarrhea incidence and serum interleukin (IL)-6 content (P < 0.05). Conversely, a high dosage of 600 mg/kg IPA led to increased serum contents of tumor necrosis factor (TNF)-α, and IL-6 (P < 0.05). Optimal antioxidant benefits were observed at 100 mg/kg IPA supplementation, which significantly reduced malondialdehyde levels while enhancing serum total antioxidant capacity and total superoxide dismutase activity on d 14 (P < 0.05). Exp. 2 investigated the effects of IPA on lipopolysaccharide (LPS) challenge in weaned piglets. The study consisted of 32 weaned piglets allocated into 4 groups, with 8 replicates per group and 1 piglet per replicate: a control group, a LPS challenge group, a LPS challenge group supplemented with 100 mg/kg IPA, and a group supplemented with 100 mg/kg IPA alone. Upon administration of LPS or saline injection, the results indicated that dietary IPA supplementation in challenged piglets enhanced villus height: crypt depth, modulated IL-8 and IL-22 mRNA relative expression, and increased the tight junction protein claudin-1 mRNA relative expression in the intestinal mucosa (P < 0.05). These findings suggest that dietary supplementation of IPA at specific concentrations significantly improves growth performance, reduces diarrhea incidence, and mitigates inflammation and oxidative stress in weaned piglets. It may be concluded that incorporating IPA into the diet of weaned piglets can effectively improve their health and development.