While beneficial for sow reproductive efficiency and biosecurity, segregated early weaning (SEW) leads to a systemic immune response that adversely affects the digestive physiology and post-weaning growth of pigs. Two experiments were conducted to evaluate the effects of a glucocorticoid receptor agonist (GA) on growth performance, measures of immune function and intestinal integrity of SEW pigs. In both experiments, pigs were fed corn-soybean meal-based starter diets. In the first experiment, 48 pigs (initial BW 4.8 ± 0.7 kg) were weaned at 21 ± 1 days and randomly assigned to three GA treatment groups: 0, 0.2 and 0.6 mg GA/kg of BW injected intramuscularly. Treatments were administered one day before weaning. Pigs in the 0 mg GA group received sterile saline in place of GA. Body weight was measured daily from one day before to 7 days post-weaning, and then weekly until 28 days post-weaning. Piglets treated with 0.2 mg GA had a higher BW than piglets in other treatment groups during the 28-day course of the study (P <0.02). To further explore the mechanisms behind this result, a second experiment was performed in which a total of 18 gilts (BW 5.6 ± 0.85 kg) were randomly assigned into three treatment groups: suckling plus saline (UWS), weaned treated with GA (WGA; 0.2 mg GA/kg BW) and weaned plus saline (CON). Treatments were administered one day before and 3 days post-weaning. The WGA and CON groups were weaned at 23 ± 2 days, while the UWS group remained with sow for the duration of the study. Body weight was measured daily and blood plasma was collected at 0, 1, 4 and 5 days post-weaning. All gilts were euthanized 5 days after weaning and jejunum samples were collected for mucosal scrapings, histomorphological analysis and gene expression analysis. Plasma levels of interleukin-1β (IL-1β) and haptoglobin were lower in WGA pigs compared with CON (P <0.02), while plasma total antioxidant capacity was higher in WGA pigs compared with both CON and UWS groups (P <0.01). Relative to CON, GA downregulated IL-18 gene expression in the jejunum, as assessed by both tissue homogenate and mucosal scrapings, but it upregulated claudin-IV gene expression only in the tissue homogenate (P <0.01). These results suggest that GA treatment improves the growth performance of SEW pigs in part by mitigating the negative effects of systemic inflammation. However, the effect of GA on barrier integrity requires further investigation.