Radiation-induced gastrointestinal syndrome occurs due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of the mucosal barrier, bacterial invasion, inflammation, and sepsis. In this study, we investigated the role of ferulic acid (FA) against ionising radiation-induced duodenal injury and subsequent alterations in redox signalling events in wild type male Swiss albino mice. Mice were administered with FA at a dose of 50 mg/kg body weight for 5 consecutive days prior to exposure of 2.5, 5 and 10 Gy doses of γ-radiation. Histopathological and electron microscopic images revealed marked duodenal injuries in a dose-dependent manner. FA prevented radiation induced damage and loss of cryptic stem cells and the shortening of duodenal villus length. FA pretreatment further suppressed NF-κB-dependent activation of inflammatory pathways and augmented Nrf2 nuclear translocation with higher expression of Mn-SOD and heme-oxygenase one (HO1) activity to combat with radiation induced duodenal stress. The colocalisation of NF-κB and Nrf2 transcription factors in the nuclei of the duodenum indicated their interaction in radiation and the FA combination group. Moreover, FA treatment inhibited phosphatidyl serine (PS) externalisation, and loss of mitochondrial membrane potential in duodenal cells. Animals exposed to 10-Gy irradiation exhibited over activation of p53, p21, caspase 3, poly ADP ribose polymerase (PARP) and DNA double-strand break which were ameliorated by FA treatment. Therefore, this article first uncovers the modulatory effect of FA on radiation-induced ROS/NF-κB/Nrf2/p53-caspase 3-PARP axis in the duodenum and establishing biological function of FA in protecting duodenum from radiation damage with a detailed mechanistic approach. © 2017 Informa UK Limited, trading as Taylor & Francis Group.