Inflammation and oxidative stress pathways have emerged as novel targets in the management of inflammatory bowel diseases (IBD). Targeting the drug to the inflamed colon remains a challenge. Nanostructured lipid carriers (NLCs) have been reported to accumulate in inflamed colonic mucosa. The antioxidant/antiinflamatory polyphenol oleuropein (OLE) was loaded in NLCs (NLC-OLE). NLC-OLE showed to be more effective in decreasing the TNF-α secretion and intracellular reactive oxygen species (ROS) by activated macrophages (J774) compared to the conventional form of OLE. OLE efficacy was preserved within NLC-OLE ameliorating inflammation in a murine model of acute colitis: reduced levels of TNF-α and IL-6, decreased neutrophil infiltration and improved histopathology of the colon were reported. In addition, NLC-OLE enhanced the ROS scavenging activity of OLE in the colon after oral administration. These data suggest that the proposed NLC-OLE could be a promising drug delivery system for OLE in IBD treatment.Copyright © 2020 Elsevier B.V. All rights reserved.