Abstract Protocatechuic acid (PCA), a phenolic acid that occurs widely in plants, is believed to be the major potential bioactive metabolites of cyanidin 3-glucoside against oxidative stress and inflammation, which are major causes of intestinal injury in weaned piglets. This study aimed to investigate the effect of PCA on growth performance, inflammatory status and immune indices in lipopolysaccharide (LPS)-challenged weaned piglets. Thirty six 21-day-old weaned PIC piglets were housed in pairs in cages with one ripple drinker and one hopper type feeder, and randomly allocated into 3 dietary treatments with 6 replicates per treatment and 2 piglets per replicate after fed a control diet for 7 days. The treatments were: control diets (CTL), CTL+50 ppm aureomycin, CTL+4000 ppm PCA, based on our pilot tests. The period of experiment was 21 days, and piglets were challenged by intraperitoneal injection of LPS (10 μg/kg) at day 14 and day 21. Blood samples were obtained from eighteen piglets (one from each replicate) one hour after LPS injection on day 21, and inflammatory cytokines, antioxidant capacity index, and immune indices were measured in blood serum. The results revealed that the average daily gain of piglets was increased by supplementing with PCA (P = 0.036), but not aureomycin (P = 0.184). Dietary supplement with PCA decreased serum levels of inflammatory cytokines including interleukin (IL)-1β (P < 0.05), IL-2 (P < 0.05), IL-6 (P < 0.05) and tumor necrosis factor alpha (TNF-α) (P < 0.05), while aureomycin only decreased IL-6 (P < 0.05) and TNF-α (P < 0.05). Both PCA and aureomycin attenuated lipid peroxidation with a lower level of thiobarbituric acid reactive substances (P < 0.05), but increased serum levels of immunoglobulin M (P < 0.05) and C-reactive protein (P < 0.05) in piglets. These data suggested that PCA may improve growth performance and immunity of weaned piglets, and thus can be a potential alternative for antibiotics in animal feeds.