This study was designed to evaluate the hepato and neuroprotective activity of Daflon and low-dose radiation on thioacetamide (TAA)-induced liver damage and hepatic encephalopathy (HE) in rats. Effect of daily Daflon treatment (100 mg/kg body weight, Per OS (p.o.) for consecutive 3 days) and/or fractionated low-dose -radiation (LDR; 0.25 Gy, twice the total dose of 0.5 Gy at the 1st and 3rd day, respectively) was evaluated against TAA (300 mg/kg, intraperitoneal x 3) induced liver damage and HE in rats. Serum aspartate transaminase, alanine transaminase, -glutamyltransferase, total bilirubin, ammonia, and manganese were estimated to evaluate liver function. In addition, malondialdehyde (MDA) as well as reduced glutathione (GSH), glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) were determined to assess antioxidant capacity in liver tissue. Moreover, hepatic apoptotic markers (cysteine-dependent aspartate-directed proteases 3, 8 (caspase-3, 8) and cytochrome C) were estimated to indicate hepatic apoptosis. HE was evaluated through the determination of whole brain ammonia, manganese, MDA, GSH, GPX, SOD, CAT, and caspase-3. The cognitive and locomotor deficits were assessed via step through passive avoidance test, activity cage (actophotometer), -aminobutyric acid, and N-methyl-d-aspartate/adenosine triphosphate–neuronal nitric oxide synthase/nitric oxide–cyclic guanosine monophosphate axis in rats’ cerebella and hippocampi. The involvement of hypoxia inducible factor-1α, aquaporine-4, and matrix metalloproteinase 9 in association with the brain water content (%) in the whole brain as an index for brain edema was also evaluated. The obtained results showed a marked amelioration of the aforementioned biochemical parameters and behavioral tasks which is supported by histopathological and immunohistochemical examination. It could be concluded that Daflon and LDR afforded hepatoprotection and neuroprotection against TAA-induced acute liver damage and HE.