The effects of monolaurin (ML) on the health of piglets infected with porcine epidemic diarrhoea virus (PEDV) have not been fully understood. This study aimed to investigate its role in blood biochemical profile, intestinal barrier function, antioxidant function and the expression of antiviral genes in piglets infected with PEDV. Thirty-two piglets were randomly divided into four groups: control group, ML group, PEDV group and ML + PEDV group. Piglets were orally administrated with ML at a dose of 100 mg/kg·BW for 7 d before PEDV infection. Results showed that PEDV infection significantly decreased D-xylose content and increased intestinal fatty acid-binding protein content, indicating that PEDV infection destroyed intestinal barrier and absorption function. While it could be repaired by ML administration. Moreover, ML administration significantly decreased plasma blood urea nitrogen and total protein content upon PEDV infection. These results suggested ML may increase protein utilisation efficiency. ML administration significantly decreased the number of large unstained cells and Hb and increased the number of leucocytes and eosinophils in the blood of PEDV-infected piglets, indicating ML could improve the immune defense function of the body. In the presence of PEDV infection, ML administration significantly increased superoxide dismutase and catalase activities in blood and colon, respectively, indicating ML could improve antioxidant capacity. Besides, ML administration reversed the expression of ISG15, IFIT3 and IL-29 throughout the small intestine and Mx1 in jejunum and ileum, indicating the body was in recovery from PEDV infection. This study suggests that ML could be used as a kind of feed additive to promote swine health upon PEDV infection.