Ginseng-derived nanoparticles (GDNPs) alleviate inflammatory bowel disease (IBD) by targeting the TLR4/MAPK and p62/Nrf2/Keap1 pathways. This study investigated the therapeutic potential of GDNPs in IBD, focusing on their effects on macrophages, intestinal epithelial cells, intestinal stem cells, and the intestinal microenvironment. GDNPs were found to scavenge reactive oxygen species (ROS) from immune cells and intestinal epithelial cells, inhibit pro-inflammatory factors, promote intestinal stem cell proliferation and differentiation, and enhance intestinal flora diversity. These actions stabilize the intestinal barrier, promote tissue repair, and reduce inflammation and oxidative stress in both in vitro and in vivo models. GDNPs significantly reduced inflammatory factors and improved the intestinal environment in mice, suggesting their potential as a novel therapeutic strategy for IBD. The study highlights the role of GDNPs in activating the body's first line of defense through anti-inflammatory and antioxidant pathways, including the TLR4/MAPK and p62/Nrf2/Keap1 pathways. Additionally, GDNPs promote the Wnt/β-catenin signaling pathway, enhancing intestinal stem cell proliferation and differentiation. The results indicate that GDNPs can alleviate DSS-induced IBD by activating Nrf2 and inhibiting the MAPK signaling pathway, reducing inflammation and oxidative stress. GDNPs also regulate the intestinal microbiota, maintaining microbiome homeostasis and improving the Firmicutes/Bacteroidetes ratio. The study demonstrates that GDNPs are safe and effective in vivo, with no significant toxicity observed in mice. Overall, GDNPs show promise as a novel therapeutic approach for IBD due to their ability to modulate multiple pathways involved in inflammation and oxidative stress.Ginseng-derived nanoparticles (GDNPs) alleviate inflammatory bowel disease (IBD) by targeting the TLR4/MAPK and p62/Nrf2/Keap1 pathways. This study investigated the therapeutic potential of GDNPs in IBD, focusing on their effects on macrophages, intestinal epithelial cells, intestinal stem cells, and the intestinal microenvironment. GDNPs were found to scavenge reactive oxygen species (ROS) from immune cells and intestinal epithelial cells, inhibit pro-inflammatory factors, promote intestinal stem cell proliferation and differentiation, and enhance intestinal flora diversity. These actions stabilize the intestinal barrier, promote tissue repair, and reduce inflammation and oxidative stress in both in vitro and in vivo models. GDNPs significantly reduced inflammatory factors and improved the intestinal environment in mice, suggesting their potential as a novel therapeutic strategy for IBD. The study highlights the role of GDNPs in activating the body's first line of defense through anti-inflammatory and antioxidant pathways, including the TLR4/MAPK and p62/Nrf2/Keap1 pathways. Additionally, GDNPs promote the Wnt/β-catenin signaling pathway, enhancing intestinal stem cell proliferation and differentiation. The results indicate that GDNPs can alleviate DSS-induced IBD by activating Nrf2 and inhibiting the MAPK signaling pathway, reducing inflammation and oxidative stress. GDNPs also regulate the intestinal microbiota, maintaining microbiome homeostasis and improving the Firmicutes/Bacteroidetes ratio. The study demonstrates that GDNPs are safe and effective in vivo, with no significant toxicity observed in mice. Overall, GDNPs show promise as a novel therapeutic approach for IBD due to their ability to modulate multiple pathways involved in inflammation and oxidative stress.